Substituted Phenylureas and Phenylamides as Vanilloid Receptor Ligands

ABSTRACT

The invention relates to substituted phenylureas and phenylamides, to processes for the preparation thereof, to pharmaceutical compositions containing these compounds and also to the use of these compounds for preparing pharmaceutical compositions.

This application which claims priority under 35 U.S.C. §119(e) to U.S.Provisional Patent Application No. 61/176,284, filed on May 7, 2009, andalso claims priority under 35 U.S.C. §119(a) to European Application No.09 006 237.3, filed May 7, 2009. The contents of both applications arehereby incorporated by reference in their entirety.

The invention relates to substituted phenylureas and phenylamides, toprocesses for the preparation thereof, to pharmaceutical compositionscontaining these compounds and also to the use of these compounds forpreparing pharmaceutical compositions.

The treatment of pain, in particular of neuropathic pain, is veryimportant in medicine. There is a worldwide demand for effective paintherapies. The urgent need for action for a patient-focused andtarget-oriented treatment of chronic and non-chronic states of pain,this being understood to mean the successful and satisfactory treatmentof pain for the patient, is also documented in the large number ofscientific studies which have recently appeared in the field of appliedanalgesics or basic research on nociception.

The subtype 1 vanilloid receptor (VR1/TRPV1), which is often alsoreferred to as the capsaicin receptor, is a suitable starting point forthe treatment of pain, in particular of pain selected from the groupconsisting of acute pain, chronic pain, neuropathic pain and visceralpain, particularly preferably of neuropathic pain. This receptor isstimulated inter alia by vanilloids such as capsaicin, heat and protonsand plays a central role in the formation of pain. In addition, it isimportant for a large number of further physiological andpathophysiological processes and is a suitable target for the therapy ofa large number of further disorders such as, for example, migraine,depression, neurodegenerative diseases, cognitive disorders, states ofanxiety, epilepsy, coughs, diarrhoea, pruritus, inflammations, disordersof the cardiovascular system, eating disorders, medication dependency,misuse of medication and in particular urinary incontinence.

There is a demand for further compounds having comparable or betterproperties, not only with regard to affinity to vanilloid receptors 1(VR1/TRPV1 receptors) per se (potency, efficacy).

Thus, it may be advantageous to improve the metabolic stability, thesolubility in aqueous media or the permeability of the compounds. Thesefactors can have a beneficial effect on oral bioavailability or canalter the PK/PD (pharmacokinetic/pharmacodynamic) profile; this can leadto a more beneficial period of effectiveness, for example.

A weak or non-existent interaction with transporter molecules, which areinvolved in the ingestion and the excretion of pharmaceuticalcompositions, is also to be regarded as an indication of improvedbioavailability and at most low interactions of pharmaceuticalcompositions. Furthermore, the interactions with the enzymes involved inthe decomposition and the excretion of pharmaceutical compositionsshould also be as low as possible, as such test results also suggestthat at most low interactions, or no interactions at all, ofpharmaceutical compositions are to be expected.

It was therefore an object of the invention to provide new compoundshaving advantages over the prior-art compounds. The compounds should besuitable in particular as pharmacological active ingredients inpharmaceutical compositions, preferably in pharmaceutical compositionsfor the treatment and/or prophylaxis of disorders or diseases which aremediated, at least in some cases, by vanilloid receptors 1 (VR1/TRPV1receptors).

This object is achieved by the subject matter of the claims.

Now, it has surprisingly been found that the substituted compounds ofgeneral formula (I), as indicated below, display outstanding affinity tothe subtype 1 vanilloid receptor (VR1/TRPV1 receptor) and are thereforeparticularly suitable for the prophylaxis and/or treatment of disordersor diseases which are mediated, at least in some cases, by vanilloidreceptors 1 (VR1/TRPV1). The substituted compounds of general formula(I), as indicated below, also have anti-inflammatory activity.

The present invention therefore relates to substituted compounds ofgeneral formula (I),

in which

-   X represents CR³ or N,    -   wherein R³ represents H; C₁₋₁₀ alkyl, saturated or unsaturated,        branched or unbranched, unsubstituted or mono- or        polysubstituted;-   A represents N or CR^(5b),-   n represents 0, 1, 2, 3 or 4; preferably 1, 2, 3 or 4,-   R⁰ represents C₁₋₁₀ alkyl, saturated or unsaturated, branched or    unbranched, unsubstituted or mono- or polysubstituted; C₃₋₁₀    cycloalkyl or heterocyclyl, respectively saturated or unsaturated,    unsubstituted or mono- or polysubstituted; aryl or heteroaryl,    respectively unsubstituted or mono- or polysubstituted; C₃₋₁₀    cycloalkyl or heterocyclyl bridged via C₁₋₈ alkyl, respectively    saturated or unsaturated, unsubstituted or mono- or polysubstituted,    wherein the alkyl chain can be respectively branched or unbranched,    saturated or unsaturated, unsubstituted, mono- or polysubstituted;    or aryl or heteroaryl bridged via C₁₋₈ alkyl, respectively    unsubstituted or mono- or polysubstituted, wherein the alkyl chain    can be respectively branched or unbranched, saturated or    unsaturated, unsubstituted, mono- or polysubstituted;-   R¹ represents H; C₁₋₁₀ alkyl, saturated or unsaturated, branched or    unbranched, unsubstituted or mono- or polysubstituted; C₃₋₁₀    cycloalkyl¹ or heterocyclyl¹, respectively saturated or unsaturated,    unsubstituted or mono- or polysubstituted; aryl or heteroaryl,    respectively unsubstituted or mono- or polysubstituted; C₃₋₁₀    cycloalkyl or heterocyclyl¹ bridged via C₁₋₈ alkyl, respectively    saturated or unsaturated, unsubstituted or mono- or polysubstituted,    wherein the alkyl chain can be respectively branched or unbranched,    saturated or unsaturated, unsubstituted, mono- or polysubstituted;    or aryl or heteroaryl bridged via C₁₋₈ alkyl, respectively    unsubstituted or mono- or polysubstituted, wherein the alkyl chain    can be respectively branched or unbranched, saturated or    unsaturated, unsubstituted, mono- or polysubstituted; C(═O)—R⁰;    C(═O)—OH; C(═O)—OR⁰; C(═O)—NHR⁰; C(═O)—N(R⁰)₂; OH; O—R⁰; SH; S—R⁰;    S(═O)₂—R⁰; S(═O)₂—OR⁰; S(═O)₂—NHR⁰; S(═O)₂—N(R⁰)₂; NH₂; NHR⁰;    N(R⁰)₂; NH—S(═O)₂—R⁰; N(R⁰)(S(═O)₂—R⁰); or SCl₃; preferably    represents C₁₋₁₀ alkyl, saturated or unsaturated, branched or    unbranched, unsubstituted or mono- or polysubstituted; C₃₋₁₀    cycloalkyl¹ or heterocyclyl¹, respectively saturated or unsaturated,    unsubstituted or mono- or polysubstituted; aryl or heteroaryl,    respectively unsubstituted or mono- or polysubstituted; C₃₋₁₀    cycloalkyl¹ or heterocyclyl¹ bridged via C₁₋₈ alkyl, respectively    saturated or unsaturated, unsubstituted or mono- or polysubstituted,    wherein the alkyl chain can be respectively branched or unbranched,    saturated or unsaturated, unsubstituted, mono- or polysubstituted;    or aryl or heteroaryl bridged via C₁₋₈ alkyl, respectively    unsubstituted or mono- or polysubstituted, wherein the alkyl chain    can be respectively branched or unbranched, saturated or    unsaturated, unsubstituted, mono- or polysubstituted; C(═O)—R⁰;    C(═O)—OH; C(═O)—OR⁰; C(═O)—NHR⁰; C(═O)—N(R⁰)₂; OH; O—R⁰; SH; S—R⁰;    S(═O)₂—R⁰; S(═O)₂—OR⁰; S(═O)₂—NHR⁰; S(═O)₂—N(R⁰)₂; NH₂; NHR⁰;    N(R⁰)₂; NH—S(═O)₂—R⁰; N(R⁰)(S(═O)₂—R⁰); or SCl₃;-   R² represents H; R⁰; F; Cl; Br; I; CN; NO₂; OH; SH; CF₃; CF₂H; CFH₂;    CF₂Cl; CFCl₂; CH₂CF₃; OCF₃; OCF₂H; OCFH₂; OCF₂Cl; OCFCl₂; SCF₃;    SCF₂H; SCFH₂; SCF₂Cl; SCFCl₂; S(═O)₂—CF₃; S(═O)₂—CF₂H; S(═O)₂—CFH₂;    or SF₅; preferably represents H; R⁰; F; I; CN; NO₂; OH; SH; CF₃;    CF₂H; CFH₂; CF₂Cl; CFCl₂; CH₂CF₃; OCF₃; OCF₂H; OCFH₂; OCF₂Cl;    OCFCl₂; SCF₃; SCF₂H; SCFH₂; SCF₂Cl; SCFCl₂; S(═O)₂—CF₃; S(═O)₂—CF₂H;    S(═O)₂—CFH₂; or SF₅;-   R⁴ represents H; F; Cl; Br; I; OH; C₁₋₁₀ alkyl, saturated or    unsaturated, branched or unbranched, unsubstituted or mono- or    polysubstituted;-   R^(5a) represents H; OH; C₁₋₁₀ alkyl, saturated or unsaturated,    branched or unbranched, unsubstituted or mono- or polysubstituted;-   R^(5b) represents H; or R⁰;

or R^(5a) and R^(5b) form together with the carbon atom connecting thema C₃₋₁₀ cycloalkyl or a heterocyclyl, respectively saturated orunsaturated, unsubstituted or mono- or polysubstituted;

R⁶, R⁷, R⁸, R⁹ and R¹⁰ each independently of one another represent H; F;Cl; Br; I; NO₂; CN; CF₃; CF₂H; CFH₂; CF₂Cl; CFCl₂; R⁰; C(═O)H; C(═O)R⁰;CO₂H; C(═O)OR⁰; CONH₂; C(═O)NHR⁰; C(═O)N(R⁰)₂; OH; OCF₃; OCF₂H; OCFH₂;OCF₂Cl; OCFCl₂; OR⁰; O—C(═O)—R⁰; O—C(═O)—O—R⁰; O—(C═O)—NH—R⁰;O—C(═O)—N(R⁰)₂; O—S(═O)₂—R⁰; O—S(═O)₂OH; O—S(═O)₂OR⁰; O—S(═O)₂NH₂;O—S(═O)₂NHR⁰; O—S(═O)₂N(R⁰)₂; NH₂; NH—R⁰; N(R⁰)₂; NH—C(═O)—R⁰;NH—C(═O)—O—R⁰; NH—C(═O)—NH₂; NH—C(═O)—NH—R⁰; NH—C(═O)—N(R⁰)₂;NR⁰—C(═O)—R⁰; NR⁰—C(═O)—O—R⁰; NR⁰—C(═O)—NH₂; NR⁰—C(═O)—NH—R⁰;NR⁰—C(═O)—N(R⁰)₂; NH—S(═O)₂OH; NH—S(═O)₂R⁰; NH—S(═O)₂OR⁰; NH—S(═O)₂NH₂;NH—S(═O)₂NHR⁰; NH—S(═O)₂N(R⁰)₂; NR⁰—S(═O)₂OH; NR⁰—S(═O)₂R⁰;NR⁰—S(═O)₂OR⁰; NR⁰—S(═O)₂NH₂; NR⁰—S(═O)₂NHR⁰; NR⁰—S(═O)₂N(R⁰)₂; SH;SCF₃; SCF₂H; SCFH₂; SCF₂Cl; SCFCl₂; SR⁰; S(═O)R⁰; S(═O)₂R⁰; S(═O)₂OH;S(═O)₂OR⁰; S(═O)₂NH₂; S(═O)₂NHR⁰; or S(═O)₂N(R⁰)₂;

preferably R⁶, R⁷, R⁹ and R¹⁰ each independently of one anotherrepresent H; F; Cl; Br; I; NO₂; CN; CF₃; CF₂H; CFH₂; CF₂Cl; CFCl₂; R⁰;C(═O)H; C(═O)R⁰; CO₂H; C(═O)OR⁰; CONH₂; C(═O)NHR⁰; C(═O)N(R⁰)₂; OH;OCF₃; OCF₂H; OCFH₂; OCF₂Cl; OCFCl₂; OR⁰; O—C(═O)—R⁰; O—C(═O)—O—R⁰;O—(C═O)—NH—R⁰; O—C(═O)—N(R⁰)₂; O—S(═O)₂—R⁰; O—S(═O)₂OH; O—S(═O)₂OR⁰;O—S(═O)₂NH₂; O—S(═O)₂NHR⁰; O—S(═O)₂N(R⁰)₂; NH₂; NH—R⁰; N(R⁰)₂;NH—C(═O)—R⁰; NH—C(═O)—O—R⁰; NH—C(═O)—NH₂; NH—C(═O)—NH—R⁰;NH—C(═O)—N(R⁰)₂; NR⁰—C(═O)—R⁰; NR⁰—C(═O)—O—R⁰; NR⁰—C(═O)—NH₂;NR⁰—C(═O)—NH—R⁰; NR⁰—C(═O)—N(R⁰)₂; NH—S(═O)₂OH; NH—S(═O)₂R⁰;NH—S(═O)₂OR⁰; NH—S(═O)₂NH₂; NH—S(═O)₂NHR⁰; NH—S(═O)₂N(R⁰)₂;NR⁰—S(═O)₂OH; NR⁰—S(═O)₂R⁰; NR⁰—S(═O)₂OR⁰; NR⁰—S(═O)₂NH₂;NR⁰—S(═O)₂NHR⁰; NR⁰—S(═O)₂N(R⁰)₂; SH; SCF₃; SCF₂H; SCFH₂; SCF₂Cl;SCFCl₂; SR⁰; S(═O)R⁰; S(═O)₂R⁰; S(═O)₂OH; S(═O)₂OR⁰; S(═O)₂NH₂;S(═O)₂NHR⁰; or S(═O)₂N(R⁰)₂;

preferably R⁸ represents H; F; Cl; Br; I; NO₂; CN; CF₃; CF₂H; CFH₂;CF₂Cl; CFCl₂; R⁰; C(═O)H; C(═O)R⁰; CO₂H; C(═O)OR⁰; CONH₂; C(═O)NHR⁰;C(═O)N(R⁰)₂; OH; OCF₃; OCF₂H; OCFH₂; OCF₂Cl; OCFCl₂; OR⁰; O—C(═O)—R⁰;O—C(═O)—O—R⁰; O—(C═O)—NH—R⁰; O—C(═O)—N(R⁰)₂; O—S(═O)₂—R⁰; O—S(═O)₂OH;O—S(═O)₂OR⁰; O—S(═O)₂NH₂; O—S(═O)₂NHR⁰; O—S(═O)₂N(R⁰)₂; NH₂; NH—R⁰;N(R⁰)₂; NH—C(═O)—R⁰; NH—C(═O)—O—R⁰; NH—C(═O)—NH₂; NH—C(═O)—NH—R⁰;NH—C(═O)—N(R⁰)₂; NR⁰—C(═O)—R⁰; NR⁰—C(═O)—O—R⁰; NR⁰—C(═O)—NH₂;NR⁰—C(═O)—NH—R⁰; NR⁰—C(═O)—N(R⁰)₂; NH—S(═O)₂OH; NH—S(═O)₂R⁰;NH—S(═O)₂OR⁰; NH—S(═O)₂NH₂; NH—S(═O)₂NHR⁰; NH—S(═O)₂N(R⁰)₂;NR⁰—S(═O)₂OH; NR⁰—S(═O)₂R⁰; NR⁰—S(═O)₂OR⁰; NR⁰—S(═O)₂NH₂;NR⁰—S(═O)₂NHR⁰; NR⁰—S(═O)₂N(R⁰)₂; SH; SCF₃; SCF₂H; SCFH₂; SCF₂Cl;SCFCl₂; SR⁰; S(═O)R⁰; S(═O)₂R⁰; S(═O)₂OH; S(═O)₂OR⁰; S(═O)₂NH₂;S(═O)₂NHR⁰; or S(═O)₂N(R⁰)₂; wherein, if R⁸ denotes R⁰ and R⁰ representsheteroaryl, said heteroaryl is selected from the group consisting ofbenzofuranyl, benzoimidazolyl, benzothienyl, benzothiadiazolyl,benzothiazolyl, benzotriazolyl, benzooxazolyl, benzooxadiazolyl,quinazolinyl, quinoxalinyl, carbazolyl, quinolinyl, dibenzofuranyl,dibenzothienyl, furyl (furanyl), imidazothiazolyl, indazolyl,indolizinyl, indolyl, isoquinolinyl, isoxazoyl, isothiazolyl, indolyl,naphthyridinyl, oxazolyl, oxadiazolyl, phenazinyl, phenothiazinyl,phthalazinyl, pyrazolyl, pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl),pyrrolyl, pyridazinyl, pyrimidinyl, pyrazinyl, purinyl, phenazinyl,thienyl (thiophenyl), triazolyl, tetrazolyl, thiazolyl, thiadiazolyl andtriazinyl;

in which “substituted alkyl”, “substituted heterocyclyl” and“substituted cycloalkyl” relate, with respect to the correspondingresidues, to the substitution of one or more hydrogen atoms eachindependently of one another by F; Cl; Br; I; NO₂; CN; ═O; ═NH;═C(NH₂)₂; CF₃; CF₂H; CFH₂; CF₂Cl; CFCl₂; R⁰; C(═O)H; C(═O)R⁰; CO₂H;C(═O)OR⁰; CONH₂; C(═O)NHR⁰; C(═O)N(R⁰)₂; OH; OCF₃; OCF₂H; OCFH₂; OCF₂Cl;OCFCl₂; OR⁰; O—C(═O)—R⁰; O—C(═O)—O—R⁰; O—(C═O)—NH—R⁰; O—C(═O)—N(R⁰)₂;O—S(═O)₂—R⁰; O—S(═O)₂OH; O—S(═O)₂OR⁰; O—S(═O)₂NH₂; O—S(═O)₂NHR⁰;O—S(═O)₂N(R⁰)₂; NH₂; NH—R⁰; N(R⁰)₂; NH—C(═O)—R⁰; NH—C(═O)—O—R⁰;NH—C(═O)—NH₂; NH—C(═O)—NH—R⁰; NH—C(═O)—N(R⁰)₂; NR⁰—C(═O)—R⁰;NR⁰—C(═O)—O—R⁰; NR⁰—C(═O)—NH₂; NR⁰—C(═O)—NH—R⁰; NR⁰—C(═O)—N(R⁰)₂;NH—S(═O)₂OH; NH—S(═O)₂R⁰; NH—S(═O)₂OR⁰; NH—S(═O)₂NH₂; NH—S(═O)₂NHR⁰;NH—S(═O)₂N(R⁰)₂; NR⁰—S(═O)₂OH; NR⁰—S(═O)₂R⁰; NR⁰—S(═O)₂OR⁰;NR⁰—S(═O)₂NH₂; NR⁰—S(═O)₂NHR⁰; NR⁰—S(═O)₂N(R⁰)₂; SH; SCF₃; SCF₂H; SCFH₂;SCF₂Cl; SCFCl₂; SR⁰; S(═O)R⁰; S(═O)₂R⁰; S(═O)₂OH; S(═O)₂OR⁰; S(═O)₂NH₂;S(═O)₂NHR⁰; or S(═O)₂N(R⁰)₂;

in which “substituted cycloalkyl¹” and “substituted heterocyclyl¹”relate, with respect to the corresponding residues, to the substitutionof one or more hydrogen atoms each independently of one another by F;Cl; Br; I; NO₂; CN; ═O; ═C(NH₂)₂; CF₃; CF₂H; CFH₂; CF₂Cl; CFCl₂; R⁰;C(═O)H; C(═O)R⁰; CO₂H; C(═O)OR⁰; CONH₂; C(═O)NHR⁰; C(═O)N(R⁰)₂; OH;OCF₃; OCF₂H; OCFH₂; OCF₂Cl; OCFCl₂; OR⁰; O—C(═O)—R⁰; O—C(═O)—O—R⁰;O—(C═O)—NH—R⁰; O—C(═O)—N(R⁰)₂; O—S(═O)₂—R⁰; O—S(═O)₂OH; O—S(═O)₂OR⁰;O—S(═O)₂NH₂; O—S(═O)₂NHR⁰; O—S(═O)₂N(R⁰)₂; SH; SCF₃; SCF₂H; SCFH₂;SCF₂Cl; SCFCl₂; SR⁰; S(═O)R⁰; S(═O)₂R⁰; S(═O)₂OH; S(═O)₂OR⁰; S(═O)₂NH₂;S(═O)₂NHR⁰; or S(═O)₂N(R⁰)₂;

in which “substituted aryl” and “substituted heteroaryl” relate, withrespect to the corresponding residues, to the substitution of one ormore hydrogen atoms each independently of one another by F; Cl; Br; I;NO₂; CN; CF₃; CF₂H; CFH₂; CF₂Cl; CFCl₂; R⁰; C(═O)H; C(═O)R⁰; CO₂H;C(═O)OR⁰; CONH₂; C(═O)NHR⁰; C(═O)N(R⁰)₂; OH; OCF₃; OCF₂H; OCFH₂; OCF₂Cl;OCFCl₂; OR⁰; O—C(═O)—R⁰; O—C(═O)—O—R⁰; O—(C═O)—NH—R⁰; O—C(═O)—N(R⁰)₂;O—S(═O)₂—R⁰; O—S(═O)₂OH; O—S(═O)₂OR⁰; O—S(═O)₂NH₂; O—S(═O)₂NHR⁰;O—S(═O)₂N(R⁰)₂; NH₂; NH—R⁰; N(R⁰)₂; NH—C(═O)—R⁰; NH—C(═O)—O—R⁰;NH—C(═O)—NH₂; NH—C(═O)—NH—R⁰; NH—C(═O)—N(R⁰)₂; NR⁰—C(═O)—R⁰;NR⁰—C(═O)—O—R⁰; NR⁰—C(═O)—NH₂; NR⁰—C(═O)—NH—R⁰; NR⁰—C(═O)—N(R⁰)₂;NH—S(═O)₂OH; NH—S(═O)₂R⁰; NH—S(═O)₂OR⁰; NH—S(═O)₂NH₂; NH—S(═O)₂NHR⁰;NH—S(═O)₂N(R⁰)₂; NR⁰—S(═O)₂OH; NR⁰—S(═O)₂R⁰; NR⁰—S(═O)₂OR⁰;NR⁰—S(═O)₂NH₂; NR⁰—S(═O)₂NHR⁰; NR⁰—S(═O)₂N(R⁰)₂; SH; SCF₃; SCF₂H; SCFH₂;SCF₂Cl; SCFCl₂; SR⁰; S(═O)R⁰; S(═O)₂R⁰; S(═O)₂OH; S(═O)₂OR⁰; S(═O)₂NH₂;S(═O)₂NHR⁰; or S(═O)₂N(R⁰)₂;

preferably in which “substituted aryl” relates, with respect to thecorresponding residues, to the substitution of one or more hydrogenatoms each independently of one another by F; Cl; Br; I; NO₂; CF₃; CF₂H;CFH₂; CF₂Cl; CFCl₂; R⁰; C(═O)H; C(═O)R⁰; CO₂H; C(═O)OR⁰; CONH₂;C(═O)NHR⁰; C(═O)N(R⁰)₂; OH; OCF₃; OCF₂H; OCFH₂; OCF₂Cl; OCFCl₂; OR⁰;O—C(═O)—R⁰; O—C(═O)—O—R⁰; O—(C═O)—NH—R⁰; O—C(═O)—N(R⁰)₂; O—S(═O)₂—R⁰;O—S(═O)₂OH; O—S(═O)₂OR⁰; O—S(═O)₂NH₂; O—S(═O)₂NHR⁰; O—S(═O)₂N(R⁰)₂; NH₂;NH—R⁰; N(R⁰)₂; NH—C(═O)—R⁰; NH—C(═O)—O—R⁰; NH—C(═O)—NH₂; NH—C(═O)—NH—R⁰;NH—C(═O)—N(R⁰)₂; NR⁰—C(═O)—R⁰; NR⁰—C(═O)—O—R⁰; NR⁰—C(═O)—NH₂;NR⁰—C(═O)—NH—R⁰; NR⁰—C(═O)—N(R⁰)₂; NH—S(═O)₂OH; NH—S(═O)₂R⁰;NH—S(═O)₂OR⁰; NH—S(═O)₂NH₂; NH—S(═O)₂NHR⁰; NH—S(═O)₂N(R⁰)₂;NR⁰—S(═O)₂OH; NR⁰—S(═O)₂R⁰; NR⁰—S(═O)₂OR⁰; NR⁰—S(═O)₂NH₂;NR⁰—S(═O)₂NHR⁰; NR⁰—S(═O)₂N(R⁰)₂; SH; SCF₃; SCF₂H; SCFH₂; SCF₂Cl;SCFCl₂; SR⁰; S(═O)R⁰; S(═O)₂R⁰; S(═O)₂OH; S(═O)₂OR⁰; S(═O)₂NH₂;S(═O)₂NHR⁰; or S(═O)₂N(R⁰)₂;

preferably in which ““substituted heteroaryl” relates, with respect tothe corresponding residues, to the substitution of one or more hydrogenatoms each independently of one another by F; Cl; Br; I; NO₂; CN; CF₃;CF₂H; CFH₂; CF₂Cl; CFCl₂; R⁰; C(═O)H; C(═O)R⁰; CO₂H; C(═O)OR⁰; CONH₂;C(═O)NHR⁰; C(═O)N(R⁰)₂; OH; OCF₃; OCF₂H; OCFH₂; OCF₂Cl; OCFCl₂; OR⁰;O—C(═O)—R⁰; O—C(═O)—O—R⁰; O—(C═O)—NH—R⁰; O—C(═O)—N(R⁰)₂; O—S(═O)₂—R⁰;O—S(═O)₂OH; O—S(═O)₂OR⁰; O—S(═O)₂NH₂; O—S(═O)₂NHR⁰; O—S(═O)₂N(R⁰)₂; NH₂;NH—R⁰; N(R⁰)₂; NH—C(═O)—R⁰; NH—C(═O)—O—R⁰; NH—C(═O)—NH₂; NH—C(═O)—NH—R⁰;NH—C(═O)—N(R⁰)₂; NR⁰—C(═O)—R⁰; NR⁰—C(═O)—O—R⁰; NR⁰—C(═O)—NH₂;NR⁰—C(═O)—NH—R⁰; NR⁰—C(═O)—N(R⁰)₂; NH—S(═O)₂OH; NH—S(═O)₂R⁰;NH—S(═O)₂OR⁰; NH—S(═O)₂NH₂; NH—S(═O)₂NHR⁰; NH—S(═O)₂N(R⁰)₂;NR⁰—S(═O)₂OH; NR⁰—S(═O)₂R⁰; NR⁰—S(═O)₂OR⁰; NR⁰—S(═O)₂NH₂;NR⁰—S(═O)₂NHR⁰; NR⁰—S(═O)₂N(R⁰)₂; SH; SCF₃; SCF₂H; SCFH₂; SCF₂Cl;SCFCl₂; SR⁰; S(═O)R⁰; S(═O)₂R⁰; S(═O)₂OH; S(═O)₂OR⁰; S(═O)₂NH₂;S(═O)₂NHR⁰; or S(═O)₂N(R⁰)₂;

in the form of the free compounds; the tautomers; the N-oxides; theracemate; the enantiomers, diastereomers, mixtures of the enantiomers ordiastereomers or of an individual enantiomer or diastereomer; or in theform of the salts of physiologically compatible acids or bases; or ifappropriate in the form of solvates.

The terms “alkyl” or “C₁₋₁₀ alkyl”, “C₁₋₈ alkyl”, “C₁₋₆ alkyl”, “C₁₋₄alkyl” comprise in the sense of this invention acyclic saturated orunsaturated aliphatic hydrocarbon residues, i.e. C₁₋₁₀ aliphaticresidues, C₁₋₈ aliphatic residues, C₁₋₆ aliphatic residues and C₁₋₄aliphatic residues, which can be respectively branched or unbranched andalso unsubstituted or mono- or polysubstituted, containing 1 to 10 or 1to 8 or 1 to 6 or 1 to 4 carbon atoms, i.e. C₁₋₁₀ alkanyls, C₂₋₁₀alkenyls and C₂₋₁₀ alkinyls or C₁₋₈ alkanyls, C₂₋₈ alkenyls and C₂₋₈alkinyls or C₁₋₆ alkanyls, C₂₋₆ alkenyls and C₂₋₆ alkinyls or C₁₋₄alkanyls, C₂₋₄ alkenyls and C₂₋₄ alkinyls. In this case, alkenylscomprise at least one C—C double bond and alkinyls comprise at least oneC—C triple bond. Preferably, alkyl is selected from the group comprisingmethyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec.-butyl,tert.-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-heptyl, n-octyl,n-nonyl, n-decyl, ethenyl (vinyl), ethinyl, propenyl (—CH₂CH═CH₂,—CH═CH—CH₃, —C(═CH₂)—CH₃), propinyl (—CH—C—CH, —C≡C—CH₃), butenyl,butinyl, pentenyl, pentinyl, hexenyl and hexinyl, heptenyl, heptinyl,octenyl, octinyl, nonenyl, noninyl, decenyl and decinyl.

The terms “cycloalkyl” or “C₃₋₁₀ cycloalkyl” and “cycloalkyl¹” or “C₃₋₁₀cycloalkyl¹” mean for the purposes of this invention cyclic aliphatic(cycloaliphatic) hydrocarbons containing 3, 4, 5, 6, 7, 8, 9 or 10carbon atoms, i.e. C₃₋₁₀-cycloaliphatic residues, wherein thehydrocarbons can be saturated or unsaturated (but not aromatic),unsubstituted or mono- or polysubstituted. The cycloalkyl can be boundto the respective superordinate general structure via any desired andpossible ring member of the cycloalkyl residue. The cycloalkyl residuescan also be condensed with further saturated, (partially) unsaturated,(hetero)cyclic, aromatic or heteroaromatic ring systems, i.e. withcycloalkyl, heterocyclyl, aryl or heteroaryl which can in turn beunsubstituted or mono- or polysubstituted. The cycloalkyl residues canfurthermore be singly or multiply bridged such as, for example, in thecase of adamantyl, bicyclo[2.2.1]heptyl or bicyclo[2.2.2]octyl.Preferably, cycloalkyl is selected from the group comprisingcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclononyl, cyclodecyl, adamantyl,

cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.

The terms “heterocyclyl” or “heterocycloalkyl” and “heterocyclyl¹” or“heterocycloalkyl¹” comprise aliphatic saturated or unsaturated (but notaromatic) cycloalkyls having three to ten, i.e. 3, 4, 5, 6, 7, 8, 9 or10, ring members, in which at least one, if appropriate also two orthree carbon atoms are replaced by a heteroatom or a heteroatom groupeach selected independently of one another from the group consisting ofO, S, S(═O)₂, N, NH and N(C₁₋₈ alkyl), preferably N(CH₃), wherein thering members can be unsubstituted or mono- or polysubstituted.Heterocyclyls are thus heterocycloaliphatic residues. The heterocyclylcan be bound to the superordinate general structure via any desired andpossible ring member of the heterocyclyl residue. The heterocyclylresidues can therefore be condensed with further saturated, (partially)unsaturated (hetero)cyclic or aromatic or heteroaromatic ring systems,i.e. with cycloalkyl, heterocyclyl, aryl or heteroaryl which can in turnbe unsubstituted or mono- or polysubstituted. Heterocyclyl residues fromthe group comprising azetidinyl, aziridinyl, azepanyl, azocanyl,diazepanyl, dithiolanyl, dihydroquinolinyl, dihydropyrrolyl, dioxanyl,dioxolanyl, dioxepanyl, dihydroindenyl, dihydropyridinyl,dihydrofuranyl, dihydroisoquinolinyl, dihydroindolinyl,dihydroisoindolyl, imidazolidinyl, isoxazolidinyl, morpholinyl,oxiranyl, oxetanyl, pyrrolidinyl, piperazinyl, 4-methylpiperazinyl,piperidinyl, pyrazolidinyl, pyranyl, tetrahydropyrrolyl,tetrahydropyranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,tetrahydroindolinyl, tetrahydrofuranyl, tetrahydropyridinyl,tetrahydrothiophenyl, tetrahydropyridoindolyl, tetrahydronaphthyl,tetrahydrocarbolinyl, tetrahydroisoxazolopyridinyl, thiazolidinyl andthiomorpholinyl are preferred.

The term “aryl” means in the sense of this invention aromatichydrocarbons having up to 14 ring members, including phenyls andnaphthyls. Each aryl residue can be unsubstituted or mono- orpolysubstituted, wherein the aryl substituents can be the same ordifferent and in any desired and possible position of the aryl. The arylcan be bound to the superordinate general structure via any desired andpossible ring member of the aryl residue. The aryl residues can also becondensed with further saturated, (partially) unsaturated,(hetero)cyclic, aromatic or heteroaromatic ring systems, i.e. withcycloalkyl, heterocyclyl, aryl or heteroaryl which can in turn beunsubstituted or mono- or polysubstituted. Examples of condensed arylresidues are benzodioxolanyl and benzodioxanyl. Preferably, aryl isselected from the group containing phenyl, 1-naphthyl and 2-naphthylwhich can be respectively unsubstituted or mono- or polysubstituted. Aparticularly preferred aryl is phenyl, unsubstituted or mono- orpolysubstituted.

The term “heteroaryl” represents a 5 or 6-membered cyclic aromaticresidue containing at least 1, if appropriate also 2, 3, 4 or 5heteroatoms, wherein the heteroatoms are each selected independently ofone another from the group S, N and O and the heteroaryl residue can beunsubstituted or mono- or polysubstituted; in the case of substitutionon the heteroaryl, the substituents can be the same or different and bein any desired and possible position of the heteroaryl. The binding tothe superordinate general structure can be carried out via any desiredand possible ring member of the heteroaryl residue. The heteroaryl canalso be part of a bi- or polycyclic system having up to 14 ring members,wherein the ring system can be formed with further saturated,(partially) unsaturated, (hetero)cyclic or aromatic or heteroaromaticrings, i.e. with cycloalkyl, heterocyclyl, aryl or heteroaryl which canin turn be unsubstituted or mono- or polysubstituted. It is preferablefor the heteroaryl residue to be selected from the group comprisingbenzofuranyl, benzoimidazolyl, benzothienyl, benzothiadiazolyl,benzothiazolyl, benzotriazolyl, benzooxazolyl, benzooxadiazolyl,quinazolinyl, quinoxalinyl, carbazolyl, quinolinyl, dibenzofuranyl,dibenzothienyl, furyl (furanyl), imidazolyl, imidazothiazolyl,indazolyl, indolizinyl, indolyl, isoquinolinyl, isoxazoyl, isothiazolyl,indolyl, naphthyridinyl, oxazolyl, oxadiazolyl, phenazinyl,phenothiazinyl, phthalazinyl, pyrazolyl, pyridyl (2-pyridyl, 3-pyridyl,4-pyridyl), pyrrolyl, pyridazinyl, pyrimidinyl, pyrazinyl, purinyl,phenazinyl, thienyl (thiophenyl), triazolyl, tetrazolyl, thiazolyl,thiadiazolyl or triazinyl. Furyl, pyridyl and thienyl are particularlypreferred.

The terms “aryl, heteroaryl, heterocyclyl, cycloalkyl, heterocyclyl¹ orcycloalkyl¹ bridged via C₁₋₄ alkyl or C₁₋₈ is alkyl” mean in the senseof the invention that C₁₋₄ alkyl or C₁₋₈ is alkyl and aryl or heteroarylor heterocyclyl or cycloalkyl or heterocyclyl¹ or cycloalkyl¹ have theabove-defined meanings and the aryl or heteroaryl or heterocyclyl orcycloalkyl or heterocyclyl¹ or cycloalkyl¹ residue is bound to therespective superordinate general structure via a C₁₋₄ alkyl or a C₁₋₈alkyl group. The alkyl chain of the alkyl group can in all cases bebranched or unbranched, unsubstituted or mono- or polysubstituted. Thealkyl chain of the alkyl group can furthermore be in all cases saturatedor unsaturated, i.e. can be an alkylene group, i.e. a C₁₋₄ alkylenegroup or a C₁₋₈ alkylene group, an alkenylene group, i.e. a C₂₋₄alkenylene group or a C₂₋₈ alkenylene group, or an alkinylene group,i.e. a C₂₋₄ alkinylene group or a C₂₋₈ alkinylene group. Preferably,C₁₋₄ alkyl is selected from the group comprising —CH₂—, —CH₂—CH₂—,—CH(CH₃)—, —CH₂—CH₂—CH₂—, —CH(CH₃)—CH₂—, —CH(CH₂CH₃)—, —CH₂—(CH₂)₂—CH₂—,—CH(CH₃)—CH₂—CH₂—, —CH₂—CH(CH₃)—CH₂—, —CH(CH₃)—CH(CH₃)—,—CH(CH₂CH₃)—CH₂—, —C(CH₃)₂—CH₂—, —CH(CH₂CH₂CH₃)—, —C(CH₃)(CH₂CH₃)—,—CH═CH—, —CH═CH—CH₂—, —C(CH₃)═CH₂—, —CH═CH—CH₂—CH₂—, —CH₂—CH═CH—CH₂—,—CH═CH—CH═CH—, —C(CH₃)═CH—CH₂—, —CH═C(CH₃)—CH₂—, —C(CH₃)═C(CH₃)—,—C(CH₂CH₃)═CH—, —C≡C—, —C≡C—CH₂—, —C≡C—CH₂—CH₂—, —C≡C—CH(CH₃)—,—CH₂—C≡C—CH₂— and —C≡C—C≡C— and C₁₋₈ alkyl is selected from the groupcomprising —CH₂—, —CH₂—CH₂—, —CH(CH₃)—, —CH₂—CH₂—CH₂—, —CH(CH₃)—CH₂—,—CH(CH₂CH₃)—, —CH₂—(CH₂)₂—CH₂—, —CH(CH₃)—CH₂—CH₂—, —CH₂—CH(CH₃)—CH₂—,—CH(CH₃)—CH(CH₃)—, —CH(CH₂CH₃)—CH₂—, —C(CH₃)₂—CH₂—, —CH(CH₂CH₂CH₃)—,—C(CH₃)(CH₂CH₃)—, —CH₂—(CH₂)₃—CH₂—, —CH(CH₃)—CH₂—CH₂—CH₂—,—CH₂—CH(CH₃)—CH₂—CH₂—, —CH(CH₃)—CH₂—CH(CH₃)—, —CH(CH₃)—CH(CH₃)—CH₂—,—C(CH₃)₂—CH₂—CH₂—, —CH₂—C(CH₃)₂—CH₂—, —CH(CH₂CH₃)—CH₂—CH₂—,—CH₂—CH(CH₂CH₃)—CH₂—, —C(CH₃)₂—CH(CH₃)—, —CH(CH₂CH₃)—CH(CH₃)—,—C(CH₃)(CH₂CH₃)—CH₂—, —CH(CH₂CH₂CH₃)—CH₂—, —C(CH₂CH₂CH₃)—CH₂—,—CH(CH₂CH₂CH₂CH₃)—, —C(CH₃)(CH₂CH₂CH₃)—, —C(CH₂CH₃)₂—, —CH₂—(CH₂)₄—CH₂—,—CH═CH—, —CH═CH—CH₂—, —C(CH₃)═CH₂—, —CH═CH—CH₂—CH₂—, —CH₂—CH═CH—CH₂—,—CH═CH—CH═CH—, —C(CH₃)═CH—CH₂—, —CH═C(CH₃)—CH₂—, —C(CH₃)═C(CH₃)—,—C(CH₂CH₃)═CH—, —CH═CH—CH₂—CH₂—CH₂—, —CH₂—CH═CH₂—CH₂—CH₂—,—CH═CH═CH—CH₂—CH₂—, —CH═CH₂—CH—CH═CH₂—, —C≡C—, —C≡C—CH₂—, —C≡C—CH₂—CH₂—,—C≡C—CH(CH₃)—, —CH₂—C≡C—CH₂—, —C≡C—C≡C—, —C≡C—C(CH₃)₂—,—C≡C—CH₂—CH₂—CH₂—, —CH₂—C≡C—CH₂—CH₂—, —C≡C—C≡C—CH₂— and —C≡C—CH₂—C≡C—.

In relation to “alkyl”, “heterocyclyl” and “cycloalkyl”, the term “mono-or polysubstituted” refers in the sense of this invention to the singleor multiple, for example double, triple or quadruple, substitution ofone or more hydrogen atoms each independently of one another bysubstituents selected from the group of F; Cl; Br; I; NO₂; CN; ═O; ═NH;═C(NH₂)₂; CF₃;

CF₂H; CFH₂; CF₂Cl; CFCl₂; R⁰; C(═O)H; C(═O)R⁰; CO₂H; C(═O)OR⁰; CONH₂;C(═O)NHR⁰;

C(═O)N(R⁰)₂; OH; OCF₃; OCF₂H; OCFH₂; OCF₂Cl; OCFCl₂; OR⁰; O—C(═O)—R⁰;O—C(═O)—O—R⁰; O—(C═O)—NH—R⁰; O—C(═O)—N(R⁰)₂; O—S(═O)₂—R⁰; O—S(═O)₂OH;O—S(═O)₂OR⁰; O—S(═O)₂NH₂; O—S(═O)₂NHR⁰; O—S(═O)₂N(R⁰)₂; NH₂; NH—R⁰;N(R⁰)₂; NH—C(═O)—R⁰; NH—C(═O)—O—R⁰; NH—C(═O)—NH₂; NH—C(═O)—NH—R⁰;NH—C(═O)—N(R⁰)₂; NR⁰—C(═O)—R⁰; NR⁰—C(═O)—O—R⁰; NR⁰—C(═O)—NH₂;NR⁰—C(═O)—NH—R⁰; NR⁰—C(═O)—N(R⁰)₂; NH—S(═O)₂OH; NH—S(═O)₂R⁰;NH—S(═O)₂OR⁰; NH—S(═O)₂NH₂; NH—S(═O)₂NHR⁰; NH—S(═O)₂N(R⁰)₂;NR⁰—S(═O)₂OH; NR⁰—S(═O)₂R⁰; NR⁰—S(═O)₂OR⁰; NR⁰—S(═O)₂NH₂;NR⁰—S(═O)₂NHR⁰; NR⁰—S(═O)₂N(R⁰)₂; SH; SCF₃; SCF₂H; SCFH₂; SCF₂Cl;SCFCl₂; SR⁰; S(═O)R⁰; S(═O)₂R⁰; S(═O)₂OH; S(═O)₂OR⁰; S(═O)₂NH₂;S(═O)₂NHR⁰; or S(═O)₂N(R⁰)₂; wherein the term “polysubstituted residues”refers to residues of the type that are polysubstituted, for exampledi-, tri- or tetrasubstituted, either on different or on the same atoms,for example trisubstituted on the same C atom, as in the case of CF₃ orCH₂CF₃, or at various points, as in the case of CH(OH)—CH═CH—CHC₂. Asubstituent can if appropriate for its part in turn be mono- orpolysubstituted. The multiple substitution can be carried out using thesame or using different substituents.

In relation to “cycloalkyl¹” and “heterocyclyl¹”, the term “mono- orpolysubstituted” refers in the sense of this invention to the single ormultiple, for example double, triple or quadruple, substitution of oneor more hydrogen atoms each independently of one another by substituentsselected from the group of F; Cl; Br; I; NO₂; CN; ═O; ═C(NH₂)₂; CF₃;CF₂H; CFH₂; CF₂Cl; CFCl₂; R⁰; C(═O)H; C(═O)R⁰; CO₂H; C(═O)OR⁰; CONH₂;C(═O)NHR⁰; C(═O)N(R⁰)₂; OH; OCF₃; OCF₂H; OCFH₂; OCF₂Cl; OCFCl₂; OR⁰;O—C(═O)—R⁰; O—C(═O)—O—R⁰; O—(C═O)—NH—R⁰; O—C(═O)—N(R⁰)₂; O—S(═O)₂—R⁰;O—S(═O)₂OH; O—S(═O)₂OR⁰; O—S(═O)₂NH₂; O—S(═O)₂NHR⁰; O—S(═O)₂N(R⁰)₂; SH;SCF₃; SCF₂H; SCFH₂; SCF₂Cl; SCFCl₂; SR⁰; S(═O)R⁰; S(═O)₂R⁰; S(═O)₂OH;S(═O)₂OR⁰; S(═O)₂NH₂; S(═O)₂NHR⁰; or S(═O)₂N(R⁰)₂; wherein the term“polysubstituted residues” refers to residues of the type that aremultiply, for example di-, tri- or tetrasubstituted, either on differentor on the same atoms, for example trisubstituted on the same C atom, asin the case of 1,1-difluorocyclohexyl, or at various points, as in thecase of 1,2-difluorocyclohexyl. A substituent can if appropriate for itspart in turn be mono- or polysubstituted. The multiple substitution canbe carried out using the same or using different substituents.

Preferred “alkyl”, “heterocyclyl” and “cycloalkyl” substituents areselected from the group of F; Cl; Br; I; NO₂; CF₃; CN; ═O; ═NH; R⁰;C(═O)(R⁰ or H); C(═O)O(R⁰ or H); C(═O)N(R⁰ or H)₂; OH; OR⁰; O—C(═O)—R⁰;O—(C₁₋₈ is alkyl)-OH; O—(C₁₋₈ is alkyl)-O—C₁₋₈ alkyl; OCF₃; N(R⁰ or H)₂;N(R⁰ or H)—C(═O)—R⁰; N(R⁰ or H)—C(═O)—N(R⁰ or H)₂; SH; SCF₃; SR⁰;S(═O)₂R⁰; S(═O)₂O(R⁰ or H) and S(═O)₂—N(R⁰ or H)₂.

Particularly preferred “alkyl”, “heterocyclyl” and “cycloalkyl”substituents are selected from the group consisting of F; Cl; Br; I;NO₂; CF₃; CN; ═O; C₁₋₈ alkyl; aryl; heteroaryl; C₃₋₁₀ cycloalkyl;heterocyclyl; aryl, heteroaryl, C₃₋₁₀ cycloalkyl or heterocyclyl bridgedvia C₁₋₈ alkyl; CHO; C(═O)C₁₋₈ alkyl; C(═O)aryl; C(═O)heteroaryl; CO₂H;C(═O)O—C₁₋₈ alkyl; C(═O)O-aryl; C(═O)O-heteroaryl; CONH₂; C(═O)NH—C₁₋₈alkyl; C(═O)N(C₁₋₈ alkyl)₂; C(═O)NH-aryl; C(═O)N(aryl)₂;C(═O)NH-heteroaryl; C(═O)N(heteroaryl)₂; C(═O)N(C₁₋₈ alkyl)(aryl);C(═O)N(C₁₋₈ alkyl)(heteroaryl); C(═O)N(heteroaryl)(aryl); OH; O—C₁₋₈alkyl; OCF₃; O—(C₁₋₈ alkyl)-OH; O—(C₁₋₈ alkyl)-O—C₁₋₈ alkyl; O-benzyl;O-aryl; O-heteroaryl; O—C(═O)C₁₋₈ alkyl; O—C(═O)aryl; O—C(═O)heteroaryl;NH₂; NH—C₁₋₈ alkyl; N(C₁₋₈ alkyl)₂; NH—C(═O)C₁₋₈ alkyl; NH—C(═O)-aryl;NH—C(═O)-heteroaryl; SH; S—C₁₋₈ alkyl; SCF₃; S-benzyl; S-aryl;S-heteroaryl; S(═O)₂C₁₋₈ alkyl; S(═O)₂ aryl; S(═O)₂ heteroaryl;S(═O)₂OH; S(═O)₂O—C₁₋₈ alkyl; S(═O)₂O-aryl; S(═O)₂O-heteroaryl;S(═O)₂—NH—C₁₋₈ alkyl; S(═O)₂—NH-aryl; and S(═O)₂—NH—C₁₋₈ heteroaryl.

Preferred “cycloalkyl¹” and “heterocyclyl¹” substituents are selectedfrom the group of F; Cl; Br; I; NO₂; CF₃; CN; ═O; R⁰; C(═O)(R⁰ or H);C(═O)O(R⁰ or H); C(═O)N(R⁰ or H)₂; OH; OR⁰; O—C(═O)—R⁰; O—(C₁₋₈alkyl)-OH; O—(C₁₋₈ alkyl)-O—C₁₋₈ alkyl; OCF₃; SH; SCF₃; SR⁰; S(═O)₂R⁰;S(═O)₂O(R⁰ or H) and S(═O)₂—N(R⁰ or H)₂.

Particularly preferred “cycloalkyl¹” and “heterocyclyl¹” substituentsare selected from the group consisting of F; Cl; Br; I; NO₂; CF₃; CN;═O; C₁₋₈ alkyl; aryl; heteroaryl; C₃₋₁₀ cycloalkyl; heterocyclyl; aryl,heteroaryl, C₃₋₁₀ cycloalkyl or heterocyclyl bridged via C₁₋₈ alkyl;CHO; C(═O)C₁₋₈ alkyl; C(═O)aryl; C(═O)heteroaryl; CO₂H; C(═O)O—C₁₋₈alkyl; C(═O)O-aryl; C(═O)O-heteroaryl; CONH₂; C(═O)NH—C₁₋₈ alkyl;C(═O)N(C₁₋₈ alkyl)₂; C(═O)NH-aryl; C(═O)N(aryl)₂; C(═O)NH-heteroaryl;C(═O)N(heteroaryl)₂; C(═O)N(C₁₋₈ alkyl)(aryl); C(═O)N(C₁₋₈alkyl)(heteroaryl); C(═O)N(heteroaryl)(aryl); OH; O—C₁₋₈ alkyl; OCF₃;O—(C₁₋₈ alkyl)-OH; O—(C₁₋₈ alkyl)-O—C₁₋₈ alkyl; O-benzyl; O-aryl;O-heteroaryl; O—C(═O)C₁₋₈ alkyl; O—C(═O)aryl; O—C(═O)heteroaryl; SH;S—C₁₋₈ alkyl; SCF₃; S-benzyl; S-aryl; S-heteroaryl; S(═O)₂C₁₋₈ alkyl;S(═O)₂aryl; S(═O)₂ heteroaryl; S(═O)₂OH; S(═O)₂O—C₁₋₈ alkyl;S(═O)₂O-aryl; S(═O)₂O-heteroaryl; S(═O)₂—NH—C₁₋₈ alkyl; S(═O)₂—NH-aryl;and S(═O)₂—NH—C₁₋₈ heteroaryl.

In relation to “aryl” and “heteroaryl”, the term “mono- orpolysubstituted” refers in the sense of this invention to the single ormultiple, for example double, triple or quadruple, substitution of oneor more hydrogen atoms of the ring system each independently of oneanother by substituents selected from the group of F; Cl; Br; I; NO₂;CN; CF₃; CF₂H; CFH₂; CF₂Cl; CFCl₂; R⁰; C(═O)H; C(═O)R⁰; CO₂H; C(═O)OR⁰;CONH₂; C(═O)NHR⁰; C(═O)N(R⁰)₂; OH; OCF₃; OCF₂H; OCFH₂; OCF₂Cl; OCFCl₂;OR⁰; O—C(═O)—R⁰; O—C(═O)—O—R⁰; O—(C═O)—NH—R⁰; O—C(═O)—N(R⁰)₂;O—S(═O)₂—R⁰; O—S(═O)₂OH; O—S(═O)₂OR⁰; O—S(═O)₂NH₂; O—S(═O)₂NHR⁰;O—S(═O)₂N(R⁰)₂; NH₂; NH—R⁰; N(R⁰)₂; NH—C(═O)—R⁰; NH—C(═O)—O—R⁰;NH—C(═O)—NH₂; NH—C(═O)—NH—R⁰; NH—C(═O)—N(R⁰)₂; NR⁰—C(═O)—R⁰;NR⁰—C(═O)—O—R⁰; NR⁰—C(═O)—NH₂; NR⁰—C(═O)—NH—R⁰; NR⁰—C(═O)—N(R⁰)₂;NH—S(═O)₂OH; NH—S(═O)₂R⁰; NH—S(═O)₂OR⁰; NH—S(═O)₂NH₂; NH—S(═O)₂NHR⁰;NH—S(═O)₂N(R⁰)₂; NR⁰—S(═O)₂OH; NR⁰—S(═O)₂R⁰; NR⁰—S(═O)₂OR⁰;NR⁰—S(═O)₂NH₂; NR⁰—S(═O)₂NHR⁰; NR⁰—S(═O)₂N(R⁰)₂; SH; SCF₃; SCF₂H; SCFH₂;SCF₂Cl; SCFCl₂; SR⁰; S(═O)R⁰; S(═O)₂R⁰; S(═O)₂OH; S(═O)₂OR⁰; S(═O)₂NH₂;S(═O)₂NHR⁰; or S(═O)₂N(R⁰)₂, on one or if appropriate different atoms,wherein a substituent can if appropriate for its part in turn be mono-or polysubstituted. The multiple substitution is carried out using thesame or using different substituents.

In a particular preferred embodiment “aryl” substituents are ≠CN.

Preferred “aryl” and “heteroaryl” substituents are F; Cl; Br; I; NO₂;CF₃; CN; R⁰; C(═O)(R⁰ or H); C(═O)O(R⁰ or H); C(═O)N(R⁰ or H)₂; OH; OR⁰;O—C(═O)—R⁰; O—(C₁₋₈ alkyl)-O—C₁₋₈ alkyl; OCF₃; N(R⁰ or H)₂; N(R⁰ orH)—C(═O)—R⁰; N(R⁰ or H)—C(═O)—N(R⁰ or H)₂; SH; SCF₃; SR⁰; S(═O)₂R⁰;S(═O)₂O(R⁰ or H); S(═O)₂—N(R⁰ or H)₂.

Particularly preferred “aryl” and “heteroaryl” substituents are selectedfrom the group consisting of F; Cl; Br; I; NO₂; CF₃; CN; C₁₋₈ alkyl;aryl; heteroaryl; C₃₋₁₀ cycloalkyl; heterocyclyl; aryl, heteroaryl,C₃₋₁₀ cycloalkyl or heterocyclyl bridged via C₁₋₈ alkyl; CHO; C(═O)C₁₋₈alkyl; C(═O)aryl; C(═O)heteroaryl; CO₂H; C(═O)O—C₁₋₈ alkyl; C(═O)O-aryl;C(═O)O-heteroaryl; CONH₂; C(═O)NH—C₁₋₈ alkyl; C(═O)N(C₁₋₈ alkyl)₂;C(═O)NH-aryl; C(═O)N(aryl)₂; C(═O)NH-heteroaryl; C(═O)N(heteroaryl)₂;C(═O)N(C₁₋₈ alkyl)(aryl); C(═O)N(C₁₋₈ alkyl)(heteroaryl);C(═O)N(heteroaryl)(aryl); OH; O—C₁₋₈ alkyl; OCF₃; O—(C₁₋₈ alkyl)-OH;O—(C₁₋₈ alkyl)-O—C₁₋₈ alkyl; O-benzyl; O-aryl; O-heteroaryl; O—C(═O)C₁₋₈alkyl; O—C(═O)aryl; O—C(═O)heteroaryl; NH₂; NH—C₁₋₈ alkyl; N(C₁₋₈alkyl)₂; NH—C(═O)C₁₋₈ alkyl; NH—C(═O)-aryl; NH—C(═O)-heteroaryl; SH;S—C₁₋₈ alkyl; SCF₃; S-benzyl; S-aryl; S-heteroaryl; S(═O)₂C₁₋₈ alkyl;S(═O)₂aryl; S(═O)₂ heteroaryl; S(═O)₂OH; S(═O)₂O—C₁₋₈ alkyl;S(═O)₂O-aryl; S(═O)₂O-heteroaryl; S(═O)₂—NH—C₁₋₈ alkyl; S(═O)₂—NH-aryl;S(═O)₂—NH—C₁₋₈ heteroaryl.

The compounds according to the invention are defined by substituents,for example by R¹, R² and R³ (1^(st) generation substituents) which arefor their part if appropriate substituted (2^(nd) generationsubstituents). Depending on the definition, these substituents of thesubstituents can for their part be resubstituted (3^(rd) generationsubstituents). If, for example, R¹=aryl (1^(st) generation substituent),then aryl can for its part be substituted, for example with C₁₋₈ alkyl(2^(nd) generation substituent). This produces the functional grouparyl-C₁₋₈ alkyl. C₁₋₈ alkyl can then for its part be resubstituted, forexample with Cl (3^(rd) generation substituent). Overall, this thenproduces the functional group aryl-C₁₋₈ alkyl-Cl.

However, in a preferred embodiment, the 3^(rd) generation substituentsmay not be resubstituted, i.e. there are then no 4^(th) generationsubstituents.

In another preferred embodiment, the 2^(nd) generation substituents maynot be resubstituted, i.e. there are then not even any 3^(rd) generationsubstituents. In other words, in this embodiment, in the case of generalformula (I), for example, the functional groups for R¹ to R¹⁰ can eachif appropriate be substituted; however, the respective substituents maythen for their part not be resubstituted.

In some cases, the compounds according to the invention are defined bysubstituents which are or carry an aryl or heteroaryl residue,respectively unsubstituted or mono- or polysubstituted, or which formtogether with the carbon atom(s) or heteroatom(s) connecting them, asthe ring member or as the ring members, a ring, for example an aryl orheteroaryl, respectively unsubstituted or mono- or polysubstituted. Boththese aryl or heteroaryl residues and the aromatic ring systems formedin this way can if appropriate be condensed with C₃₋₁₀ cycloalkyl orheterocyclyl, respectively saturated or unsaturated, or with aryl orheteroaryl, i.e. with a C₃₋₁₀ cycloalkyl such as cyclopentyl or aheterocyclyl such as morpholinyl, or an aryl such as phenyl or aheteroaryl such as pyridyl, wherein the C₃₋₁₀ cycloalkyl or heterocyclylresidues, aryl or heteroaryl residues condensed in this way can fortheir part be respectively unsubstituted or mono- or polysubstituted.

In some cases, the compounds according to the invention are defined bysubstituents which are or carry a C₃₋₁₀ cycloalkyl or heterocyclylresidue, respectively unsubstituted or mono- or polysubstituted, orwhich form together with the carbon atom(s) or heteroatom(s) connectingthem, as the ring member or as the ring members, a ring, for example aC₃₋₁₀ cycloalkyl or heterocyclyl, respectively unsubstituted or mono- orpolysubstituted. Both these C₃₋₁₀ cycloalkyl or heterocyclyl residuesand the aliphatic ring systems formed can if appropriate be condensedwith aryl or heteroaryl or with C₃₋₁₀ cycloalkyl or heterocyclyl, i.e.with an aryl such as phenyl or a heteroaryl such as pyridyl or a C₃₋₁₀cycloalkyl such as cyclohexyl or a heterocyclyl such as morpholinyl,wherein the aryl or heteroaryl residues or C₃₋₁₀ cycloalkyl orheterocyclyl residues condensed in this way can for their part berespectively unsubstituted or mono- or polysubstituted.

Within the scope of the present invention, the symbol

used in the formulae denotes a link of a corresponding residue to therespective superordinate general structure.

The term “(R⁰ or H)” within a residue means that R⁰ and H can occurwithin this residue in any possible combination. Thus, for example, theresidue “N(R⁰ or H)₂” can represent “NH₂”, “NHR⁰” and “N(R⁰)₂”. If, asin the case of “N(R⁰)₂”, R⁰ occurs multiply within a residue, then R⁰can respectively have the same or different meanings: in the presentexample of “N(R⁰)₂”, R⁰ can for example represent aryl twice, thusproducing the functional group “N(aryl)₂”, or R⁰ can represent once aryland once C₁₋₁₀ alkyl, thus producing the functional group “N(aryl)(C₁₋₁₀alkyl)”.

If a residue occurs multiply within a molecule, such as for example theresidue R⁰, then this residue can have respectively different meaningsfor various substituents: if, for example, both R¹═R⁰ and R²═R⁰, then R⁰can represent R¹=aryl and R⁰ can represent R²═C₁₋₁₀ alkyl.

The term “salt formed with a physiologically compatible acid” refers inthe sense of this invention to salts of the respective active ingredientwith inorganic or organic acids which are physiologically compatible—inparticular when used in human beings and/or other mammals. Hydrochlorideis particularly preferred. Examples of physiologically compatible acidsare: hydrochloric acid, hydrobromic acid, sulphuric acid,methanesulphonic acid, p-toluenesulphonic acid, carbonic acid, formicacid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelicacid, fumaric acid, maleic acid, lactic acid, citric acid, glutamicacid, saccharic acid, monomethylsebacic acid, 5-oxoproline,hexane-1-sulphonic acid, nicotinic acid, 2, 3 or 4-aminobenzoic acid,2,4,6-trimethylbenzoic acid, α-lipoic acid, acetyl glycine, hippuricacid, phosphoric acid, aspartic acid. Citric acid and hydrochloric acidare particularly preferred.

Physiologically compatible salts with cations or bases are salts of therespective compound—as an anion with at least one, preferably inorganic,cation—which are physiologically compatible—in particular when used inhuman beings and/or other mammals. Particularly preferred are the saltsof the alkali and alkaline earth metals but also ammonium salts[NH_(x)R_(4-x)]⁺, in which x=0, 1, 2, 3 or 4 and R represents a branchedor unbranched C₁₋₄ alkyl residue, in particular (mono-) or (di)sodium,(mono-) or (di)potassium, magnesium or calcium salts.

In preferred embodiments of the compounds according to the invention ofgeneral formula (I), n represents 1, 2, 3 or 4, preferably 1, 2 or 3,particularly preferably 1 or 2, most particularly preferably 1.

Further preferred embodiments of the compounds according to theinvention of general formula (I) have general formula (Ia), (Ib), (Ic)or (Id):

Compounds of general formulae (Ia) and (Ib) are most particularlypreferred.

In a particular preferred embodiment of the present invention R¹ is ≠H.

In a further preferred embodiment of the compounds according to theinvention of general formula (I), the residue

-   R¹ represents H; C₁₋₁₀ alkyl, C(═O)—C₁₋₁₀ alkyl, C(═O)—NH—C₁₋₁₀    alkyl, C(═O)—N(C₁₋₁₀ alkyl)₂, O—C₁₋₁₀ alkyl, S—C₁₋₁₀ alkyl, NH(C₁₋₁₀    alkyl), N(C₁₋₁₀ alkyl)₂, NH—C(═O)—C₁₋₁₀ alkyl, NH—S(═O)₂—C₁₋₁₀    alkyl, N(C₁₋₁₀ alkyl)-S(═O)₂—C₁₋₁₀ alkyl, S(═O)₂—C₁₋₁₀ alkyl,    S(═O)₂—NH—C₁₋₁₀ alkyl, S(═O)₂—N(C₁₋₁₀ alkyl)₂, in which C₁₋₁₀ alkyl    can be respectively saturated or unsaturated, branched or    unbranched, unsubstituted or mono- or polysubstituted with one or    more substituents each selected independently of one another from    the group consisting of F, Cl, Br, I, NO₂, CN, OH, ═O, O—C₁₋₄ alkyl,    OCF₃, CF₃, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, SH, S—C₁₋₄ alkyl,    SCF₃, phenyl and pyridyl, wherein phenyl or pyridyl are respectively    unsubstituted or mono- or polysubstituted with one or more    substituents each selected independently of one another from the    group consisting of F, Cl, Br, I, NO₂, CN, OH, O—C₁₋₄ alkyl, OCF₃,    C₁₋₄ alkyl, C(═O)—OH, CF₃, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, SH,    S—C₁₋₄ alkyl, SCF₃ and S(═O)₂OH;    -   or C₃₋₁₀ cycloalkyl¹ or heterocyclyl¹, respectively saturated or        unsaturated, unsubstituted or mono- or polysubstituted with one        or more substituents each selected independently of one another        from the group consisting of F, Cl, Br, I, NO₂, CN, OH, ═O,        O—C₁₋₄ alkyl, OCF₃, CF₃, SH, S—C₁₋₄ alkyl, SCF₃, phenyl and        pyridyl, wherein phenyl or pyridyl are respectively        unsubstituted or mono- or polysubstituted with one or more        substituents each selected independently of one another from the        group consisting of F, Cl, Br, I, NO₂, CN, OH, O—C₁₋₄ alkyl,        OCF₃, C₁₋₄ alkyl, C(═O)—OH, CF₃, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄        alkyl)₂, SH, S—C₁₋₄ alkyl, SCF₃ and S(═O)₂OH;    -   or C₃₋₁₀ cycloalkyl¹ or heterocyclyl¹ bridged via C₁₋₈ alkyl,        respectively saturated or unsaturated, unsubstituted or mono- or        polysubstituted with one or more substituents each selected        independently of one another from the group consisting of F, Cl,        Br, I, NO₂, CN, OH, ═O, O—C₁₋₄ alkyl, OCF₃, CF₃, SH, S—C₁₋₄        alkyl, SCF₃, phenyl and pyridyl, wherein phenyl or pyridyl are        respectively unsubstituted or mono- or polysubstituted with one        or more substituents each selected independently of one another        from the group consisting of F, Cl, Br, I, NO₂, CN, OH, O—C₁₋₄        alkyl, OCF₃, C₁₋₄ alkyl, C(═O)—OH, CF₃, NH₂, NH(C₁₋₄ alkyl),        N(C₁₋₄ alkyl)₂, SH, S—C₁₋₄ alkyl, SCF₃ and S(═O)₂OH; wherein the        alkyl chain can be respectively branched or unbranched,        saturated or unsaturated, unsubstituted, mono- or        polysubstituted with one or more substituents each selected        independently of one another from the group consisting of F, Cl,        Br; I, OH and O—C₁₋₄ alkyl;    -   or C(═O)—C₃₋₁₀ cycloalkyl, O—C₃₋₁₀ cycloalkyl, S—C₃₋₁₀        cycloalkyl, respectively saturated or unsaturated, unsubstituted        or mono- or polysubstituted with one or more substituents each        selected independently of one another from the group consisting        of F, Cl, Br, I, NO₂, CN, OH, ═O, O—C₁₋₄ alkyl, OCF₃, CF₃, NH₂,        NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, SH, S—C₁₋₄ alkyl, SCF₃, phenyl        and pyridyl, wherein phenyl or pyridyl are respectively        unsubstituted or mono- or polysubstituted with one or more        substituents each selected independently of one another from the        group consisting of F, Cl, Br, I, NO₂, CN, OH, O—C₁₋₄ alkyl,        OCF₃, C₁₋₄ alkyl, C(═O)—OH, CF₃, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄        alkyl)₂, SH, S—C₁₋₄ alkyl, SCF₃ and S(═O)₂OH;    -   or aryl, heteroaryl, C(═O)-aryl, C(═O)-heteroaryl, O-aryl,        O-heteroaryl, NH(aryl), N(aryl)₂, NH(heteroaryl),        N(heteroaryl)₂, NH—C(═O)-aryl, NH—C(═O)-heteroaryl,        NH—S(═O)₂-aryl, NH—S(═O)₂-heteroaryl, S(═O)₂-aryl,        S(═O)₂-heteroaryl or aryl or heteroaryl bridged via C₁₋₈ alkyl,        can be respectively unsubstituted or mono- or polysubstituted        with one or more substituents each selected independently of one        another from the group consisting of F, Cl, Br, I, NO₂, CN, OH,        ═O, O—C₁₋₄ alkyl, OCF₃, CF₃, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄        alkyl)₂, SH, S—C₁₋₄ alkyl, SCF₃, S(═O)₂OH and NH—S(═O)₂—C₁₋₄        alkyl, and wherein if appropriate the alkyl chain can be        respectively branched or unbranched, saturated or unsaturated,        unsubstituted, mono- or polysubstituted with one or more        substituents each selected independently of one another from the        group consisting of F, Cl, Br, I, OH and O—C₁₋₄ alkyl.

In another preferred embodiment of the compounds according to theinvention of general formula (I), the residue

R¹ represents substructure (T1)

in which

Y represents C(═O), O, S, S(═O)₂, NH—C(═O) or NR¹²

-   -   wherein R¹² represents H; C₁₋₈ alkyl or S(═O)₂—C₁₋₈ alkyl, in        which C₁₋₈ alkyl can be respectively saturated or unsaturated,        branched or unbranched, unsubstituted or mono- or        polysubstituted with one or more substituents each selected        independently of one another from the group consisting of F, Cl,        Br, I, OH, O—C₁₋₄ alkyl, OCF₃, NH₂, NH—C₁₋₄ alkyl and N(C₁₋₄        alkyl)₂;

o represents 0 or 1,

R^(11a) and R^(11b) each independently of one another represent H; F;Cl; Br; I; NO₂; CF₃; CN; OH; OCF₃; NH₂; C₁₋₄ alkyl, O—C₁₋₄ alkyl,NH—C₁₋₄ alkyl, N(C₁₋₄ alkyl)₂, in which C₁₋₄ alkyl can be respectivelysaturated or unsaturated, branched or unbranched, unsubstituted or mono-or polysubstituted with one or more substituents each selectedindependently of one another from the group consisting of F, Cl, Br, I,O—C₁₋₄ alkyl, OH and OCF₃;

-   -   on the condition that if R^(11a) and R^(11b) are bound to the        same carbon atom, only one of the substituents R^(11a) and        R^(11b) can represent OH, OCF₃, NH₂, O—C₁₋₄ alkyl, NH—C₁₋₄ alkyl        or N(C₁₋₄ alkyl)₂;

m represents 0, 1, 2, 3 or 4;

-   Z represents C₁₋₄ alkyl, saturated or unsaturated, branched or    unbranched, unsubstituted or mono- or polysubstituted with one or    more substituents each selected independently of one another from    the group consisting of F, Cl, Br, I, NO₂, CN, OH, ═O, O—C₁₋₄ alkyl,    OCF₃, C(═O)—OH, CF₃, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, SH, S—C₁₋₄    alkyl, SCF₃ and S(═O)₂OH; C₃₋₁₀ cycloalkyl¹ or heterocyclyl¹,    respectively saturated or unsaturated, unsubstituted or mono- or    polysubstituted with one or more substituents each selected    independently of one another from the group consisting of F, Cl, Br,    I, NO₂, CN, OH, O—C₁₋₄ alkyl, OCF₃, C₁₋₄ alkyl, C(═O)—OH, CF₃, SH,    S—C₁₋₄ alkyl, SCF₃, S(═O)₂OH, benzyl, phenyl, pyridyl and thienyl,    wherein benzyl, phenyl, pyridyl, thienyl can be respectively    unsubstituted or mono- or polysubstituted with one or more    substituents selected independently of one another from the group    consisting of F, Cl, Br, I, NO₂, CN, OH, O—C₁₋₄ alkyl, OCF₃, C₁₋₄    alkyl, C(═O)—OH, CF₃, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, SH,    S—C₁₋₄ alkyl, SCF₃ and S(═O)₂OH; aryl or heteroaryl, respectively    unsubstituted or mono- or polysubstituted with one or more    substituents each selected independently of one another from the    group consisting of F, Cl, Br, I, NO₂, CN, OH, O—C₁₋₄ alkyl, OCF₃,    C₁₋₄ alkyl, C(═O)—OH, CF₃, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, SH,    S—C₁₋₄ alkyl, SCF₃, S(═O)₂OH, benzyl, phenyl, pyridyl and thienyl,    wherein benzyl, phenyl, pyridyl, thienyl can be respectively    unsubstituted or mono- or polysubstituted with one or more    substituents selected independently of one another from the group    consisting of F, Cl, Br, I, NO₂, CN, OH, O—C₁₋₈ alkyl, OCF₃, C₁₋₄    alkyl, C(═O)—OH, CF₃, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, SH,    S—C₁₋₄ alkyl, SCF₃ and S(═O)₂OH.

If m≠0, then the residues R^(11a) and R^(11b) can, taking account of theforegoing condition, both on the same carbon atom and on differentcarbon atoms, each independently of one another represent H; F; Cl; Br;I; NO₂; CF₃; CN; OH; OCF₃; NH₂; C₁₋₄ alkyl, O—C₁₋₄ alkyl, NH—C₁₋₄ alkyl,N(C₁₋₄ alkyl)₂, in which C₁₋₄ alkyl can be respectively saturated orunsaturated, branched or unbranched, unsubstituted or mono- orpolysubstituted with one or more substituents each selectedindependently of one another from the group consisting of F, Cl, Br, I,O—C₁₋₄ alkyl, OH and OCF₃.

Preferably, the residue

R¹ represents substructure (T1) in which

Y represents C(═O), O, S, S(═O)₂, NH—C(═O) or NR¹²,

-   -   wherein R¹² represents H; methyl; ethyl; n-propyl; isopropyl;        n-butyl; sec.-butyl; tert.-butyl; S(═O)₂-methyl; S(═O)₂-ethyl;

o represents 0 or 1;

R^(11a) and R^(11b) each independently of one another represent H; F;Cl; Br; I; NO₂; CF₃; CN; methyl; ethyl; n-propyl; isopropyl; n-butyl;sec.-butyl; tert.-butyl; CH₂CF₃; OH; O-methyl; O-ethyl; O—(CH₂)₂—O—CH₃;O—(CH₂)₂—OH; OCF₃; NH₂; NH-methyl; N(methyl)₂; NH-ethyl; N(ethyl)₂; orN(methyl)(ethyl);

-   -   on the condition that if R^(11a) and R^(11b) are bound to the        same carbon atom, only one of the substituents R^(11a) and        R^(11b) can represent OH; OCF₃; O-methyl; O-ethyl;        O—(CH₂)₂—O—CH₃; O—(CH₂)₂—OH; NH₂; NH-methyl; N(methyl)₂;        NH-ethyl; N(ethyl)₂; or N(methyl)(ethyl);

m represents 0, 1 or 2;

-   Z represents C₁₋₄ alkyl, saturated or unsaturated, branched or    unbranched, unsubstituted or mono- or polysubstituted with one or    more substituents each selected independently of one another from    the group consisting of F, Cl, Br, I, OH, ═O, O—C₁₋₄ alkyl, OCF₃,    C(═O)—OH and CF₃; phenyl, naphthyl, furyl, pyridyl or thienyl,    respectively unsubstituted or mono- or polysubstituted with one or    more substituents each selected independently of one another from    the group consisting of F, Cl, Br, I, CN, OH, O—C₁₋₄ alkyl, OCF₃,    C₁₋₄ alkyl, CF₃, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, SH, S—C₁₋₈    alkyl, SCF₃, benzyl and phenyl, wherein benzyl and phenyl can be    respectively unsubstituted or mono- or polysubstituted with one or    more substituents selected independently of one another from the    group consisting of F, Cl, Br, I, CN, OH, O—C₁₋₄ alkyl, OCF₃, C₁₋₄    alkyl, CF₃, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, SH, S—C₁₋₄ alkyl    and SCF₃; C₃₋₁₀ cycloalkyl¹ or heterocyclyl¹, respectively saturated    or unsaturated, unsubstituted or mono- or polysubstituted with one    or more substituents each selected independently of one another from    the group consisting of F, Cl, Br, I, CN, OH, O—C₁₋₄ alkyl, OCF₃,    C₁₋₄ alkyl, CF₃, benzyl, phenyl and pyridyl, wherein benzyl, phenyl    and pyridyl can be respectively unsubstituted or mono- or    polysubstituted with one or more substituents selected independently    of one another from the group consisting of F, Cl, Br, I, CN, OH,    O—C₁₋₄ alkyl, OCF₃, C₁₋₄ alkyl, CF₃, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄    alkyl)₂, SH, S—C₁₋₄ alkyl and SCF₃.

If m≠0, then the residues R^(11a) and R^(11b) can, taking account of theforegoing condition, both on the same carbon atom and on differentcarbon atoms, each independently of one another represent H; F; Cl; Br;I; NO₂; CF₃; CN; methyl; ethyl; n-propyl; isopropyl; n-butyl;sec.-butyl; tert.-butyl; CH₂CF₃; OH; O-methyl; O-ethyl; O—(CH₂)₂—O—CH₃;O—(CH₂)₂—OH; OCF₃; NH₂; NH-methyl; N(methyl)₂; NH-ethyl; N(ethyl)₂; orN(methyl)(ethyl).

Particularly preferably, the residue

R¹ represents substructure (T1) in which

Y represents C(═O), O, S, S(═O)₂, NH—C(═O) or NR¹²,

-   -   wherein R¹² represents H; methyl; ethyl; n-propyl; isopropyl;        n-butyl; sec.-butyl; tert.-butyl; S(═O)₂-methyl; S(═O)₂-ethyl;

o represents 0 or 1;

R^(11a) and R^(11b) each independently of one another represent H; F;Cl; Br; I; methyl; ethyl; n-propyl; isopropyl; n-butyl; sec.-butyl;tert.-butyl; OH; O-methyl; O-ethyl;

-   -   on the condition that if R^(11a) and R^(11b) are bound to the        same carbon atom, only one of the substituents R^(11a) and        R^(11b) can represent OH; O-methyl; O-ethyl;

m represents 0, 1 or 2;

-   Z represents C₁₋₄ alkyl, saturated or unsaturated, branched or    unbranched, unsubstituted or mono- or polysubstituted with one or    more substituents each selected independently of one another from    the group consisting of F, Cl, Br, I, OH, O—C₁₋₄ alkyl, OCF₃, and    CF₃; C₃₋₁₀ cycloalkyl¹, saturated or unsaturated, unsubstituted or    mono- or polysubstituted with one or more substituents each selected    independently of one another from the group consisting of F, Cl, Br,    I, OH, O—C₁₋₄ alkyl, OCF₃, C₁₋₄ alkyl, CF₃, benzyl and phenyl,    wherein benzyl and phenyl can be respectively unsubstituted or mono-    or polysubstituted with one or more substituents selected    independently of one another from the group consisting of F, Cl, Br,    I, OH, O—C₁₋₄ alkyl, OCF₃, C₁₋₄ alkyl, CF₃, and SCF₃; morpholinyl,    thiomorpholinyl, piperidinyl, pyrrolidinyl, 4-methylpiperazinyl,    piperazinyl, respectively unsubstituted or mono- or polysubstituted    with one or more substituents each selected independently of one    another from the group consisting of F, Cl, Br, I, OH, O—C₁₋₄ alkyl,    OCF₃, C₁₋₄ alkyl, CF₃, benzyl and phenyl, wherein benzyl and phenyl    can be respectively unsubstituted or mono- or polysubstituted with    one or more substituents selected independently of one another from    the group consisting of F, Cl, Br, I, OH, O—C₁₋₄ alkyl, OCF₃, C₁₋₄    alkyl, CF₃ and SCF₃; phenyl, naphthyl, pyridyl or thienyl,    respectively unsubstituted or mono- or polysubstituted with one or    more substituents each selected independently of one another from    the group consisting of F, Cl, Br, I, CN, OH, O—C₁₋₄ alkyl, OCF₃,    C₁₋₄ alkyl, CF₃, SH, S—C₁₋₄ alkyl, SCF₃, benzyl and phenyl, wherein    benzyl and phenyl can be respectively unsubstituted or mono- or    polysubstituted with one or more substituents selected independently    of one another from the group consisting of F, Cl, Br, I, OH, O—C₁₋₄    alkyl, OCF₃, C₁₋₄ alkyl, CF₃ and SCF₃.

If m≠0, then the residues R^(11a) and R^(11b) can, taking account of theforegoing condition, both on the same carbon atom and on differentcarbon atoms, each independently of one another represent H; F; Cl; Br;I; methyl; ethyl; n-propyl; isopropyl; n-butyl; sec.-butyl; tert.-butyl;OH; O-methyl; O-ethyl.

Most particularly preferably, the residue

R¹ represents substructure (T1) in which

Y represents C(═O), O, S, S(═O)₂, NH—C(═O) or NR¹²,

-   -   wherein R¹² represents H; methyl; ethyl; n-propyl; isopropyl;        n-butyl; sec.-butyl; tert.-butyl; S(═O)₂-methyl;

o represents 0 or 1;

R^(11a) and R^(11b) each independently of one another represent H;methyl; ethyl; n-propyl; isopropyl; n-butyl; sec.-butyl; tert.-butyl;

m represents 0, 1 or 2;

-   Z represents C₁₋₄ alkyl, saturated or unsaturated, branched or    unbranched, unsubstituted or mono- or polysubstituted with one or    more substituents each selected independently of one another from    the group consisting of F, Cl, Br, I, OH, O—C₁₋₄ alkyl; C₃₋₁₀    cycloalkyl¹, saturated or unsaturated, morpholinyl, piperidinyl,    4-methylpiperazinyl, piperazinyl, respectively unsubstituted or    mono- or polysubstituted with one or more substituents each selected    independently of one another from the group consisting of F, Cl, Br,    I, OH, O—C₁₋₄ alkyl and C₁₋₄ alkyl; phenyl or pyridyl, respectively    unsubstituted or mono- or polysubstituted with one or more    substituents each selected independently of one another from the    group consisting of F, Cl, Br, I, CN, OH, O—C₁₋₄ alkyl, OCF₃, C₁₋₄    alkyl, CF₃, SH, S—C₁₋₄ alkyl, SCF₃.

If m≠0, then the residues R^(11a) and R^(11b) can, both on the samecarbon atom and on different carbon atoms, each independently of oneanother represent H; methyl; ethyl; n-propyl; isopropyl; n-butyl;sec.-butyl; tert.-butyl.

In a particular preferred embodiment of the present invention R² is ≠Brand ≠Cl.

In a further preferred embodiment of the compounds according to theinvention of general formula (I), the residue

-   R² represents H; F; Cl; Br; I; CN; NO₂; CF₃; CF₂H; CFH₂; CF₂Cl;    CFCl₂; OH; OCF₃; OCF₂H; OCFH₂; OCF₂Cl; OCFCl₂; SH; SCF₃; SCF₂H;    SCFH₂; SCF₂Cl; SCFCl₂; C₁₋₁₀ alkyl, saturated or unsaturated,    branched or unbranched, unsubstituted or mono- or polysubstituted    with one or more substituents each selected independently of one    another from the group consisting of F, Cl, Br, I, NO₂, CN, OH, ═O,    O—C₁₋₄ alkyl, OCF₃, C(═O)—OH, CF₃, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄    alkyl)₂, SH, S—C₁₋₄ alkyl, SCF₃ S(═O)₂OH, benzyl, phenyl, pyridyl    and thienyl, wherein benzyl, phenyl, pyridyl, thienyl can be    respectively unsubstituted or mono- or polysubstituted with one or    more substituents selected independently of one another from the    group consisting of F, Cl, Br, I, NO₂, CN, OH, O—C₁₋₄ alkyl, OCF₃,    C₁₋₄ alkyl, C(═O)—OH, CF₃, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, SH,    S—C₁₋₄ alkyl, SCF₃ and S(═O)₂OH; C₃₋₁₀ cycloalkyl or heterocyclyl,    respectively saturated or unsaturated, unsubstituted or mono- or    polysubstituted with one or more substituents selected independently    of one another from the group consisting of F, Cl, Br, I, OH, ═O,    C₁₋₄ alkyl, O—C₁₋₄ alkyl, OCF₃, C(═O)—OH and CF₃; or C₃₋₁₀    cycloalkyl or heterocyclyl bridged via C₁₋₈ alkyl, respectively    saturated or unsaturated, unsubstituted or mono- or polysubstituted    with one or more substituents each selected independently of one    another from the group consisting of F, Cl, Br, I, OH, ═O, C₁₋₄    alkyl, O—C₁₋₄ alkyl, OCF₃, C(═O)—OH and CF₃, wherein the alkyl chain    can be respectively branched or unbranched, saturated or    unsaturated, unsubstituted, mono- or polysubstituted with one or    more substituents each selected independently of one another from    the group consisting of F, Cl, Br, I, OH, ═O and O—C₁₋₄ alkyl; aryl    or heteroaryl, respectively unsubstituted or mono- or    polysubstituted with one or more substituents each selected    independently of one another from the group consisting of F, Cl, Br,    I, NO₂, CN, OH, O—C₁₋₄ alkyl, OCF₃, C₁₋₄ alkyl, C(═O)—OH, CF₃, NH₂,    NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, SH, S—C₁₋₈ alkyl, SCF₃, S(═O)₂OH,    benzyl, phenyl, pyridyl and thienyl, wherein benzyl, phenyl,    pyridyl, thienyl can be respectively unsubstituted or mono- or    polysubstituted with one or more substituents selected independently    of one another from the group consisting of F, Cl, Br, I, NO₂, CN,    OH, O—C₁₋₈ alkyl, OCF₃, C₁₋₄ alkyl, C(═O)—OH, CF₃, NH₂, NH(C₁₋₄    alkyl), N(C₁₋₄ alkyl)₂, SH, S—C₁₋₄ alkyl, SCF₃ and S(═O)₂OH; or aryl    or heteroaryl bridged via C₁₋₈ alkyl, respectively unsubstituted or    mono- or polysubstituted with one or more substituents each selected    independently of one another from the group consisting of F, Cl, Br,    I, NO₂, CN, OH, O—C₁₋₄ alkyl, OCF₃, C₁₋₄ alkyl, C(═O)—OH, CF₃, NH₂,    NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, SH, S—C₁₋₈ alkyl, SCF₃, S(═O)₂OH,    benzyl, phenyl, pyridyl and thienyl, wherein benzyl, phenyl,    pyridyl, thienyl can be respectively unsubstituted or mono- or    polysubstituted with one or more substituents selected independently    of one another from the group consisting of F, Cl, Br, I, NO₂, CN,    OH, O—C₁₋₈ alkyl, OCF₃, C₁₋₄ alkyl, C(═O)—OH, CF₃, NH₂, NH(C₁₋₄    alkyl), N(C₁₋₄ alkyl)₂, SH, S—C₁₋₄ alkyl, SCF₃ and S(═O)₂OH, wherein    the alkyl chain can be respectively branched or unbranched,    saturated or unsaturated, unsubstituted, mono- or polysubstituted    with one or more substituents each selected independently of one    another from the group consisting of F, Cl, Br, I, OH, ═O and O—C₁₋₄    alkyl.

Preferably, the residue

-   R² represents H; F; Cl; Br; I; CN; CF₃; CF₂H; CFH₂; CF₂Cl; CFCl₂;    OH; OCF₃; OCF₂H; OCFH₂; OCF₂Cl; OCFCl₂; SH; SCF₃; SCF₂H; SCFH₂;    SCF₂Cl; SCFCl₂; C₁₋₁₀ alkyl, saturated or unsaturated, branched or    unbranched, unsubstituted or mono- or polysubstituted with one or    more substituents each selected independently of one another from    the group consisting of F, Cl, Br, I, CN, OH, ═O, O—C₁₋₄ alkyl,    OCF₃, CF₃, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, SH, S—C₁₋₄ alkyl,    SCF₃; C₃₋₁₀ cycloalkyl, saturated or unsaturated, unsubstituted or    mono- or polysubstituted with one or more substituents selected    independently of one another from the group consisting of F, Cl, Br,    I, OH, ═O, C₁₋₄ alkyl, O—C₁₋₄ alkyl, OCF₃ and CF₃; or C₃₋₁₀    cycloalkyl bridged via C₁₋₈ alkyl, saturated or unsaturated,    unsubstituted or mono- or polysubstituted with one or more    substituents selected independently of one another from the group    consisting of F, Cl, Br, I, OH, ═O, C₁₋₄ alkyl, O—C₁₋₄ alkyl, OCF₃    and CF₃, wherein the alkyl chain can be respectively branched or    unbranched, saturated or unsaturated, unsubstituted; aryl or    heteroaryl, respectively unsubstituted or mono- or polysubstituted    with one or more substituents each selected independently of one    another from the group consisting of F, Cl, Br, I, CN, OH, O—C₁₋₄    alkyl, OCF₃, C₁₋₄ alkyl, CF₃, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂,    SH, S—C₁₋₈ alkyl, SCF₃, benzyl, phenyl, pyridyl and thienyl, wherein    benzyl, phenyl, pyridyl, thienyl can be respectively unsubstituted    or mono- or polysubstituted with one or more substituents selected    independently of one another from the group consisting of F, Cl, Br,    I, CN, OH, O—C₁₋₈ alkyl, OCF₃, C₁₋₄ alkyl, C(═O)—OH, CF₃, NH₂,    NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, SH, S—C₁₋₄ alkyl, SCF₃ and S(═O)₂OH;    or aryl or heteroaryl bridged via C₁₋₈ alkyl, respectively    unsubstituted or mono- or polysubstituted with one or more    substituents each selected independently of one another from the    group consisting of F, Cl, Br, I, CN, OH, O—C₁₋₄ alkyl, OCF₃, C₁₋₄    alkyl, CF₃, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, SH, S—C₁₋₈ alkyl,    SCF₃, benzyl, phenyl, pyridyl and thienyl, wherein benzyl, phenyl,    pyridyl, thienyl can be respectively unsubstituted or mono- or    polysubstituted with one or more substituents selected independently    of one another from the group consisting of F, Cl, Br, I, CN, OH,    O—C₁₋₈ alkyl, OCF₃, C₁₋₄ alkyl, C(═O)—OH, CF₃, NH₂, NH(C₁₋₄ alkyl),    N(C₁₋₄ alkyl)₂, SH, S—C₁₋₄ alkyl, SCF₃ and S(═O)₂OH, wherein the    alkyl chain can be respectively branched or unbranched, saturated or    unsaturated, unsubstituted.

Particularly preferably,

-   R² represents H; F; Cl; Br; I; CN; C₁₋₁₀ alkyl, saturated or    unsaturated, branched or unbranched, unsubstituted or mono- or    polysubstituted with one or more substituents selected independently    of one another from the group consisting of F, Cl, Br, I and OH;    C₃₋₁₀ cycloalkyl, saturated or unsaturated, unsubstituted; or C₃₋₁₀    cycloalkyl bridged via C₁₋₄ alkyl, saturated or unsaturated,    unsubstituted, wherein the alkyl chain can be branched or    unbranched, saturated or unsaturated, unsubstituted; or phenyl,    pyridyl, thienyl, respectively unsubstituted or mono- or    polysubstituted with one or more substituents selected independently    of one another from the group consisting of C₁₋₄ alkyl, O—C₁₋₄    alkyl, F, Cl, Br, I, CF₃, OCF₃, OH, SH and SCF₃; or phenyl, pyridyl    or thienyl bridged via C₁₋₄ alkyl, respectively unsubstituted or    mono- or polysubstituted with one or more substituents selected    independently of one another from the group consisting of C₁₋₄    alkyl, O—C₁₋₄ alkyl, F, Cl, Br, I, CF₃, OCF₃, OH, SH and SCF₃,    wherein the alkyl chain can be branched or unbranched, saturated or    unsaturated, unsubstituted.

Most particularly preferably, the substituent

-   R² is selected from the group consisting of H; F; Cl; Br; I; CN;    cyclopropyl; cyclobutyl; C₁₋₁₀ alkyl, saturated or unsaturated,    branched or unbranched, unsubstituted, or mono- or polysubstituted    with one or more substituents selected independently of one another    from the group consisting of F, Cl, Br; phenyl, unsubstituted or    mono- or polysubstituted with one or more substituents selected    independently of one another from the group consisting of C₁₋₄    alkyl, O—C₁₋₄ alkyl, F, Cl, Br, I, CF₃ and OCF₃.

Particularly preferably, the substituent

-   R² represents H; F; Cl; Br; I; CF₃; CN; methyl; ethyl; n-propyl;    isopropyl; n-butyl; sec.-butyl; tert.-butyl; cyclopropyl;    cyclobutyl; phenyl, unsubstituted or mono- or polysubstituted with    one or more substituents selected independently of one another from    the group consisting of C₁₋₄ alkyl, O—C₁₋₄ alkyl, F, Cl, Br, I, CF₃    and OCF₃;

Especially particularly preferably, R² represents tert.-butyl or CF₃.

In a further preferred embodiment of the compounds according to theinvention of general formula (I),

X represents CR³ or N, preferably CR³,

-   -   wherein R³ represents H; C₁₋₁₀ alkyl, saturated or unsaturated,        branched or unbranched, unsubstituted, mono- or polysubstituted        with one or more substituents each selected independently of one        another from the group consisting of F, Cl, Br, I and OH;

Preferably,

X represents CR³ or N, preferably CR³,

-   -   wherein R³ represents H; C₁₋₁₀ alkyl, saturated or unsaturated,        branched or unbranched, unsubstituted; or CF₃.

Particularly preferably,

X represents CR³ or N, preferably CR³,

-   -   wherein R³ represents H; methyl; ethyl; n-propyl; isopropyl;        n-butyl; sec.-butyl; tert.-butyl; or CF₃.

Most particularly preferably,

X represents CR³ or N, preferably CR³,

wherein R³ represents H or CH₃, most preferred H.

In a further preferred embodiment of the compounds according to theinvention of general formula (I), the residue

-   R⁴ represents H; C₁₋₁₀ alkyl, saturated or unsaturated, branched or    unbranched, unsubstituted or mono- or polysubstituted with one or    more substituents each selected independently of one another from    the group consisting of F, Cl, Br; I, OH and O—C₁₋₄ alkyl;-   A represents N or CR^(5b);-   R^(5a) represents H; OH; C₁₋₁₀ alkyl, saturated or unsaturated,    branched or unbranched, unsubstituted or mono- or polysubstituted    with one or more substituents each selected independently of one    another from the group consisting of F, Cl, Br; I, OH and O—C₁₋₄    alkyl;-   R^(5b) represents H; C₁₋₁₀ alkyl, saturated or unsaturated, branched    or unbranched, unsubstituted or mono- or polysubstituted with one or    more substituents each selected independently of one another from    the group consisting of F, Cl, Br; I, OH and O—C₁₋₄ alkyl; C₃₋₁₀    cycloalkyl or heterocyclyl, respectively saturated or unsaturated,    unsubstituted or mono- or polysubstituted with one or more    substituents each selected independently of one another from the    group consisting of F, Cl, Br; I, OH, ═O and O—C₁₋₄ alkyl; or C₃₋₁₀    cycloalkyl or heterocyclyl bridged via C₁₋₈ alkyl, respectively    saturated or unsaturated, unsubstituted or mono- or polysubstituted    with one or more substituents each selected independently of one    another from the group consisting of F, Cl, Br; I, OH, ═O and O—C₁₋₄    alkyl, wherein the alkyl chain can be respectively branched or    unbranched, saturated or unsaturated, unsubstituted, mono- or    polysubstituted with one or more substituents each selected    independently of one another from the group consisting of F, Cl, Br;    I, OH, ═O and O—C₁₋₄ alkyl; or aryl, heteroaryl, respectively    unsubstituted or mono- or polysubstituted with one or more    substituents each selected independently of one another from the    group consisting of F, Cl, Br, I, NO₂, CN, OH, O—C₁₋₄ alkyl, OCF₃,    C₁₋₄ alkyl, C(═O)—OH, CF₃, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, SH,    S—C₁₋₄ alkyl, SCF₃, S(═O)₂OH and NH—S(═O)₂—C₁₋₄ alkyl; or aryl or    heteroaryl bridged via C₁₋₈ alkyl, respectively unsubstituted or    mono- or polysubstituted with one or more substituents each selected    independently of one another from the group consisting of F, Cl, Br,    I, NO₂, CN, OH, O—C₁₋₄ alkyl, OCF₃, C₁₋₄ alkyl, C(═O)—OH, CF₃, NH₂,    NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, SH, S—C₁₋₄ alkyl, SCF₃, S(═O)₂OH and    NH—S(═O)₂—C₁₋₄ alkyl, wherein the alkyl chain can be respectively    branched or unbranched, saturated or unsaturated, unsubstituted,    mono- or polysubstituted with one or more substituents each selected    independently of one another from the group consisting of F, Cl, Br;    I, OH, ═O and O—C₁₋₄ alkyl;

or R^(5a) and R^(5b) form together with the carbon atom connecting thema C₃₋₁₀ cycloalkyl or a heterocyclyl, respectively saturated orunsaturated, unsubstituted or mono- or polysubstituted with one or moresubstituents each selected independently of one another from the groupconsisting of F, Cl, Br; I, OH, ═O and O—C₁₋₄ alkyl.

Preferably, the residue

-   R⁴ represents H; or C₁₋₁₀ alkyl, saturated or unsaturated, branched    or unbranched, unsubstituted;-   A represents N or CR^(5b);-   R^(5a) represents H; or C₁₋₁₀ alkyl, saturated or unsaturated,    branched or unbranched, unsubstituted;-   R^(5b) represents H; C₁₋₁₀ alkyl, saturated or unsaturated, branched    or unbranched, unsubstituted or mono- or polysubstituted with one or    more substituents each selected independently of one another from    the group consisting of F, Cl, Br, I, OH and O—C₁₋₄ alkyl; C₃₋₁₀    cycloalkyl, saturated or unsaturated, unsubstituted or mono- or    polysubstituted with one or more substituents each selected    independently of one another from the group consisting of F, Cl, Br,    I and C₁₋₄ alkyl; or C₃₋₁₀ cycloalkyl bridged via C₁₋₄ alkyl,    saturated or unsaturated, unsubstituted or mono- or polysubstituted    with one or more substituents each selected independently of one    another from the group consisting of F, Cl, Br, I and C₁₋₄ alkyl,    wherein the alkyl chain can be respectively branched or unbranched,    saturated or unsaturated, unsubstituted; or phenyl or pyridyl,    respectively unsubstituted or mono- or polysubstituted with one or    more substituents each selected independently of one another from    the group consisting of F, Cl, Br, I, OH, O—C₁₋₄ alkyl, OCF₃, C₁₋₄    alkyl, CF₃, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, SH, S—C₁₋₄ alkyl,    SCF₃ and NH—S(═O)₂—C₁₋₄ alkyl; or phenyl or pyridyl bridged via C₁₋₄    alkyl, respectively unsubstituted or mono- or polysubstituted with    one or more substituents each selected independently of one another    from the group consisting of F, Cl, Br, I, OH, O—C₁₋₄ alkyl, OCF₃,    C₁₋₄ alkyl, CF₃, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, SH, S—C₁₋₄    alkyl, SCF₃ and NH—S(═O)₂—C₁₋₄ alkyl, wherein the alkyl chain can be    respectively branched or unbranched, saturated or unsaturated,    unsubstituted,

or R^(5a) and R^(5b) form together with the carbon atom connecting thema C₃₋₁₀ cycloalkyl or a heterocyclyl, respectively saturated orunsaturated, unsubstituted or mono- or polysubstituted with one or moresubstituents each selected independently of one another from the groupconsisting of F, Cl, Br; I, OH, ═O and O—C₁₋₄ alkyl.

Particularly preferably, the residue

R⁴ represents H; methyl; ethyl; n-propyl; or isopropyl;

A represents N or CR^(5b);

R^(5a) represents H or CH₃, preferably H, if A represents N;

or R^(5a) represents H or CH₃, preferably H, if A represents CR^(5b),

-   -   wherein R^(5b) represents H; or C₁₋₄ alkyl, saturated or        unsaturated, branched or unbranched, unsubstituted; C₃₋₁₀        cycloalkyl, saturated or unsaturated, unsubstituted; or phenyl        or benzyl, in each case unsubstituted or mono- or        polysubstituted with one or more substituents each selected        independently of one another from the group consisting of F, Cl,        Br, I, CF₃, O—C₁₋₄ alkyl, OCF₃ and C₁₋₄ alkyl,

or R^(5a) and R^(5b) form together with the carbon atom connecting thema C₃₋₁₀ cycloalkyl, saturated or unsaturated, preferably saturated,unsubstituted or mono- or polysubstituted with one or more substituentseach selected independently of one another from the group consisting ofF, Cl, Br; I, OH, ═O and O—C₁₋₄ alkyl, preferably unsubstituted.

Most particularly preferably, the residue

A represents N or CR^(5b);

R⁴ represents H;

R^(5a) represents H;

R^(5b) represents H; or C₁₋₄ alkyl, saturated or unsaturated, branchedor unbranched, unsubstituted; cyclohexyl, unsubstituted; or phenyl orbenzyl, in each case unsubstituted or mono- or polysubstituted with oneor more substituents each selected independently of one another from thegroup consisting of F, Cl, Br, I, O—C₁₋₄ alkyl, CF₃, OCF₃ and C₁₋₄alkyl,

or R^(5a) and R^(5b) form together with the carbon atom connecting thema C₃₋₁₀ cycloalkyl, saturated or unsaturated, unsubstituted.

In a further preferred embodiment of the compounds according to theinvention of general formula (I), the residues

R⁶, R⁷, R⁸, R⁹ and R¹⁰ are each selected independently of one anotherfrom the group consisting of H; F; Cl; Br; I; CN; NO₂; CF₃; CF₂H; CFH₂;CF₂Cl; CFCl₂; OH; OCF₃; OCF₂H; OCFH₂; OCF₂Cl; OCFCl₂; SH; SCF₃; SCF₂H;SCFH₂; SCF₂Cl; SCFCl₂; NH₂; C(═O)—NH₂; C₁₋₁₀ alkyl, C₁₋₁₀ alkyl-O—C₁₋₁₀alkyl, C(═O)—NH—C₁₋₁₀ alkyl, O—C₁₋₁₀ alkyl, NH(C₁₋₁₀ alkyl), N(C₁₋₁₀alkyl)₂, NH—C(═O)—C₁₋₁₀ alkyl, N(C₁₋₁₀ alkyl)-C(═O)—C₁₋₁₀ alkyl,NH—S(═O)₂—C₁₋₁₀ alkyl, S—C₁₋₁₀ alkyl, SO₂—C₁₋₁₀ alkyl, SO₂—NH(C₁₋₁₀alkyl), SO₂—N(C₁₋₁₀ alkyl)₂, in which C₁₋₁₀ alkyl can be respectivelysaturated or unsaturated, branched or unbranched, unsubstituted or mono-or polysubstituted with one or more substituents selected independentlyof one another from the group consisting of F, Cl, Br, I, NO₂, CN, OH,O—C₁₋₄ alkyl, OCF₃, CF₃, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂,NH—S(═O)₂—C₁₋₄ alkyl, N(C₁₋₄ alkyl)-S(═O)₂—C₁₋₄ alkyl, SH, S—C₁₋₄ alkyl,S(═O)₂—C₁₋₄ alkyl and SCF₃;

C₃₋₁₀ cycloalkyl, heterocyclyl or C₃₋₁₀ cycloalkyl or heterocyclylbridged via C₁₋₈ alkyl, respectively saturated or unsaturated,unsubstituted or mono- or polysubstituted with one or more substituentsselected independently of one another from the group consisting of F,Cl, Br, I, NO₂, CN, OH, O—C₁₋₄ alkyl, OCF₃, CF₃, C₁₋₄ alkyl, NH₂,NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, NH—S(═O)₂—C₁₋₄ alkyl, N(C₁₋₄alkyl)-S(═O)₂—C₁₋₄ alkyl, SH, S—C₁₋₄ alkyl, S(═O)₂—C₁₋₄ alkyl and SCF₃,and wherein if appropriate the alkyl chain can be respectively branchedor unbranched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted with one or more substituents each selectedindependently of one another from the group consisting of F, Cl, Br; I,OH and O—C₁₋₄ alkyl;

aryl, heteroaryl, C(═O)—NH-aryl, C(═O)—NH-heteroaryl, NH—C(═O)-aryl,NH(C═O)-heteroaryl, NH(aryl), NH(heteroaryl), N(aryl)₂, N(heteroaryl)₂or aryl or heteroaryl bridged via C₁₋₈ alkyl, respectively unsubstitutedor mono- or polysubstituted with one or more substituents selectedindependently of one another from the group consisting of F, Cl, Br, I,CN, OH, O—C₁₋₄ alkyl, OCF₃, C₁₋₄ alkyl, CF₃, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄alkyl)₂, SH, S—C₁₋₄ alkyl and SCF₃, and wherein if appropriate the alkylchain can be respectively branched or unbranched, saturated orunsaturated, unsubstituted, mono- or polysubstituted with one or moresubstituents each selected independently of one another from the groupconsisting of F, Cl, Br; I, OH and O—C₁₋₄ alkyl.

In another preferred embodiment of the compounds according to theinvention of general formula (I), the residues

R⁶ and R¹⁰ each represent H.

In a further preferred embodiment of the compounds according to theinvention of general formula (I), the residues

R⁶ and R¹⁰ are each selected independently of one another from the groupconsisting of H; F; Cl; Br; I; CN; CF₃; OH; OCF₃; SH; SCF₃; C₁₋₄ alkyl,O—C₁₋₄ alkyl and NH—S(═O)₂—C₁₋₄ alkyl, in which C₁₋₄ alkyl can berespectively saturated or unsaturated, branched or unbranched,unsubstituted;

and the residues R⁷, R⁸ and R⁹ are each selected independently of oneanother from the group consisting of H; F; Cl; Br; I; CN; NO₂; CF₃; OH;OCF₃; SH; SCF₃; NH₂; C(═O)—NH₂; C₁₋₄ alkyl, C₁₋₄ alkyl-O—C₁₋₄ alkyl,C(═O)—NH—C₁₋₄ alkyl, O—C₁₋₄ alkyl, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂,NH—C(═O)—C₁₋₄ alkyl, NH—S(═O)₂—C₁₋₄ alkyl, S—C₁₋₄ alkyl, SO₂—C₁₋₄ alkyl,SO₂—NH(C₁₋₄ alkyl), SO₂—N(C₁₋₄ alkyl)₂, in which C₁₋₄ alkyl can berespectively saturated or unsaturated, branched or unbranched,unsubstituted or mono- or polysubstituted with one or more substituentsselected independently of one another from the group consisting of F,Cl, Br, I, OH, O—C₁₋₄ alkyl, OCF₃, CF₃, NH—S(═O)₂—C₁₋₄ alkyl, SH, S—C₁₋₄alkyl, S(═O)₂—C₁₋₄ alkyl and SCF₃; C₃₋₁₀ cycloalkyl, heterocyclyl orC₃₋₁₀ cycloalkyl or heterocyclyl bridged via C₁₋₈ alkyl, respectivelysaturated or unsaturated, unsubstituted or mono- or polysubstituted withone or more substituents selected independently of one another from thegroup consisting of F, Cl, Br, I, NO₂, CN, OH, O—C₁₋₄ alkyl, OCF₃, C₁₋₄alkyl, CF₃, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, NH—S(═O)₂—C₁₋₄ alkyl,N(C₁₋₄ alkyl)-S(═O)₂—C₁₋₄ alkyl, SH, S—C₁₋₄ alkyl, S(═O)₂—C₁₋₄ alkyl andSCF₃, and wherein if appropriate the alkyl chain can be respectivelybranched or unbranched, saturated or unsaturated, unsubstituted, mono-or polysubstituted with one or more substituents each selectedindependently of one another from the group consisting of F, Cl, Br; I,OH and O—C₁₋₄ alkyl; phenyl, pyridyl, furyl, thienyl, C(═O)—NH-phenyl,NH—C(═O)-phenyl, NH(phenyl), C(═O)—NH-pyridyl, NH—C(═O)-pyridyl,NH(pyridyl) or phenyl or pyridyl bridged via C₁₋₈ alkyl, wherein phenyl,pyridyl, furyl or thienyl are respectively unsubstituted or mono- orpolysubstituted with one or more substituents selected independently ofone another from the group consisting of F, Cl, Br, I, CN, OH, O—C₁₋₄alkyl, OCF₃, C₁₋₄ alkyl, CF₃, SH, S—C₁₋₄ alkyl and SCF₃, and wherein ifappropriate the alkyl chain can be respectively branched or unbranched,saturated or unsaturated, unsubstituted, mono- or polysubstituted withone or more substituents each selected independently of one another fromthe group consisting of F, Cl, Br; I, OH and O—C₁₋₄ alkyl.

Preferably,

R⁶, R⁷, R⁹ and R¹⁰ are each selected independently of one another fromthe group consisting of H; F; Cl; Br; I; CF₃; OCF₃; SCF₃; C₁₋₄ alkyl,O—C₁₋₄ alkyl and NH—S(═O)₂—C₁₋₄ alkyl, in which C₁₋₄ alkyl can berespectively saturated or unsaturated, branched or unbranched,unsubstituted;

and R⁸ is selected from the group consisting of H; F; Cl; Br; I; CN;NO₂; CF₃; OH; OCF₃; SH; SCF₃; NH₂; C(═O)—NH₂; C₁₋₄ alkyl, C₁₋₄alkyl-O—C₁₋₄ alkyl, C(═O)—NH—C₁₋₄ alkyl, O—C₁₋₄ alkyl, NH(C₁₋₄ alkyl),N(C₁₋₄ alkyl)₂, NH—C(═O)—C₁₋₄ alkyl, NH—S(═O)₂—C₁₋₄ alkyl, S—C₁₋₄ alkyl,SO₂—C₁₋₄ alkyl, SO₂—NH(C₁₋₄ alkyl), SO₂—N(C₁₋₄ alkyl)₂, in which C₁₋₄alkyl can be respectively saturated or unsaturated, branched orunbranched, unsubstituted or mono- or polysubstituted with one or moresubstituents selected independently of one another from the groupconsisting of F, Cl, Br, I, OH, O—C₁₋₄ alkyl, OCF₃, CF₃, NH—S(═O)₂—C₁₋₄alkyl, SH, S—C₁₋₄ alkyl, S(═O)₂—C₁₋₄ alkyl and SCF₃; C₃₋₁₀ cycloalkyl,heterocyclyl or C₃₋₁₀ cycloalkyl or heterocyclyl bridged via C₁₋₈ alkyl,respectively saturated or unsaturated, unsubstituted or mono- orpolysubstituted with one or more substituents selected independently ofone another from the group consisting of F, Cl, Br, I, NO₂, CN, OH,O—C₁₋₄ alkyl, OCF₃, C₁₋₄ alkyl, CF₃, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄alkyl)₂, NH—S(═O)₂—C₁₋₄ alkyl, N(C₁₋₄ alkyl)-S(═O)₂—C₁₋₄ alkyl, SH,S—C₁₋₄ alkyl, S(═O)₂—C₁₋₄ alkyl and SCF₃, and wherein if appropriate thealkyl chain can be respectively branched or unbranched, saturated orunsaturated, unsubstituted, mono- or polysubstituted with one or moresubstituents each selected independently of one another from the groupconsisting of F, Cl, Br; I, OH and O—C₁₋₄ alkyl; phenyl, pyridyl, furyl,thienyl, C(═O)—NH-phenyl, NH—C(═O)-phenyl, NH(phenyl), C(═O)—NH-pyridyl,NH—C(═O)-pyridyl, NH(pyridyl) or phenyl or pyridyl bridged via C₁₋₈alkyl, wherein phenyl, pyridyl, furyl or thienyl are respectivelyunsubstituted or mono- or polysubstituted with one or more substituentsselected independently of one another from the group consisting of F,Cl, Br, I, CN, OH, O—C₁₋₄ alkyl, OCF₃, C₁₋₄ alkyl, CF₃, SH, S—C₁₋₄ alkyland SCF₃, and wherein if appropriate the alkyl chain can be respectivelybranched or unbranched, saturated or unsaturated, unsubstituted, mono-or polysubstituted with one or more substituents each selectedindependently of one another from the group consisting of F, Cl, Br; I,OH and O—C₁₋₄ alkyl.

Particularly preferably,

-   R⁶ and R¹⁰ each represent H;-   R⁷ and R⁹ each independently of one another represent H; F; Cl; Br;    I; C₁₋₄ alkyl, O—C₁₋₄ alkyl;-   R⁸ represents H; F; Cl; Br; I; CN; NO₂; CF₃; OH; OCF₃; SH; SCF₃;    NH₂; C(═O)—NH₂; C(═O)—NH(methyl); C(═O)—NH(ethyl); C(═O)—N    (methyl)₂; C(═O)—N(ethyl)₂; C₁₋₄ alkyl, saturated or unsaturated,    branched or unbranched, unsubstituted or mono- or disubstituted with    OH; NH—C(═O)-methyl; NH—C(═O)-ethyl; CH₂—NH—S(═O)₂-methyl;

CH₂—NH—S(═O)₂-ethyl; NH—S(═O)₂-methyl; NH—S(═O)₂-ethyl; S-methyl;S-ethyl; S(═O)₂-methyl; S(═O)₂-ethyl; S(═O)₂—NH-methyl; S(═O)₂—NH-ethyl;S(═O)₂—N(methyl)₂; S(═O)₂—N(ethyl)₂; CH₂—S(═O)₂-(methyl);CH₂—S(═O)₂-ethyl); OC₁₋₄ alkyl, saturated or unsaturated, branched orunbranched, unsubstituted; C₁₋₄ alkyl-O—C₁₋₄ alkyl-O—C₁₋₄ alkyl, C₃₋₁₀cycloalkyl or C₃₋₁₀ cycloalkyl bridged via C₁₋₈ alkyl, respectivelysaturated or unsaturated, unsubstituted, and wherein if appropriate thealkyl chain can be respectively branched or unbranched, saturated orunsaturated, unsubstituted; piperidinyl; piperazinyl;4-methylpiperazinyl; morpholinyl; dioxidoisothiazolidinyl; phenyl,pyridyl, furyl, thienyl, C(═O)—NH-phenyl, NH—C(═O)-phenyl, NH(phenyl),C(═O)—NH-pyridyl, NH—C(═O)-pyridyl, NH(pyridyl), wherein phenyl,pyridyl, thienyl or furyl are respectively unsubstituted or mono- orpolysubstituted with one or more substituents selected independently ofone another from the group consisting of F, Cl, Br, I, CN, OH, O—C₁₋₄alkyl, OCF₃, C₁₋₄ alkyl, CF₃, SH, S—C₁₋₄ alkyl and SCF₃.

In a further, particularly preferred embodiment, the compounds accordingto the invention of general formula (I) have general formula (If)

in which

X represents CR³ or N,

-   -   wherein R³ represents H; methyl; ethyl; n-propyl; isopropyl;        n-butyl; sec.-butyl; tert.-butyl; or CF₃;

A represents N or CR^(5b);

R¹ represents substructure (T1)

-   -   in which    -   Y represents C(═O), O, S, S(═O)₂, NH—C(═O) or NR¹²,        -   wherein R¹² represents H; methyl; ethyl; n-propyl;            isopropyl; n-butyl; sec.-butyl; tert.-butyl; S(═O)₂-methyl;        -   o represents 0 or 1;        -   R^(11a) and R^(11b) each independently of one another            represent H; methyl; ethyl; n-propyl; isopropyl; n-butyl;            sec.-butyl; tert.-butyl;        -   m represents 0, 1 or 2;        -   Z represents C₁₋₄ alkyl, saturated or unsaturated, branched            or unbranched, unsubstituted or mono- or polysubstituted            with one or more substituents each selected independently of            one another from the group consisting of F, Cl, Br, I, OH,            O—C₁₋₄ alkyl; C₃₋₁₀ cycloalkyl¹, saturated or unsaturated,            morpholinyl, tetrahydropyranyl, piperidinyl,            4-methylpiperazinyl, piperazinyl, respectively unsubstituted            or mono- or polysubstituted with one or more substituents            each selected independently of one another from the group            consisting of F, Cl, Br, I, OH, O—C₁₋₄ alkyl and C₁₋₄ alkyl;            phenyl or pyridyl, respectively unsubstituted or mono- or            polysubstituted with one or more substituents each selected            independently of one another from the group consisting of F,            Cl, Br, I, CN, OH, O—C₁₋₄ alkyl, OCF₃, C₁₋₄ alkyl, CF₃, SH,            S—C₁₋₄ alkyl, SCF₃;

R² represents H; F; Cl; Br; I; CF₃; CN; methyl; ethyl; n-propyl;isopropyl; n-butyl; sec.-butyl; tert.-butyl; cyclopropyl; cyclobutyl;phenyl, unsubstituted or mono- or polysubstituted with one or moresubstituents selected independently of one another from the groupconsisting of C₁₋₄ alkyl, O—C₁₋₄ alkyl, F, Cl, Br, I, CF₃ and OCF₃;

R⁴ represents H; methyl; ethyl; n-propyl; or isopropyl;

R^(5a) represents H or CH₃ if A represents N; or

-   -   represents H; methyl; ethyl; n-propyl; isopropyl if A represents        CR^(5b);

-   R^(5b) represents H; methyl; ethyl; n-propyl; isopropyl;    cyclopentyl; cylohexyl; or phenyl or benzyl, in each case    unsubstituted or mono-, di- or trisubstituted with one, two or three    substituents each selected independently of one another from the    group consisting of C₁₋₄ alkyl, O—C₁₋₄ alkyl, F, Cl, Br, I, CF₃ and    OCF₃;

or R^(5a) and R^(5b) form together with the carbon atom connecting thema C₃₋₁₀ cycloalkyl, saturated or unsaturated, unsubstituted,

-   R⁷ and R⁹ each independently of one another represent H; F; Cl; Br;    I; C₁₋₄ alkyl, O—C₁₋₄ alkyl; F; Cl; Br; I;-   R⁸ represents H; F; Cl; Br; I; CN; NO₂; CF₃; OH; OCF₃; SH; SCF₃;    NH₂; C(═O)—NH₂; C(═O)—NH(methyl); C(═O)—NH(ethyl); C(═O)—N    (methyl)₂; C(═O)—N(ethyl)₂; C₁₋₄ alkyl, saturated or unsaturated,    branched or unbranched, unsubstituted or mono- or disubstituted with    OH; NH—C(═O)-methyl; NH—C(═O)-ethyl; CH₂—NH—S(═O)₂-methyl;

CH₂—NH—S(═O)₂-ethyl; NH—S(═O)₂-methyl; NH—S(═O)₂-ethyl; S-methyl;S-ethyl; S(═O)₂-methyl; S(═O)₂-ethyl; S(═O)₂—NH-methyl; S(═O)₂—NH-ethyl;S(═O)₂—N(methyl)₂; S(═O)₂—N(ethyl)₂; CH₂—S(═O)₂-methyl;CH₂—S(═O)₂-ethyl; OC₁₋₄ alkyl, saturated or unsaturated, branched orunbranched, unsubstituted; C₁₋₄ alkyl-O—C₁₋₄ alkyl-O—C₁₋₄ alkyl, C₃₋₁₀cycloalkyl, or C₃₋₁₀ cycloalkyl bridged via C₁₋₈ alkyl, respectivelysaturated or unsaturated, unsubstituted, and wherein if appropriate thealkyl chain can be respectively branched or unbranched, saturated orunsaturated, unsubstituted; piperidinyl; piperazinyl;4-methylpiperazinyl; morpholinyl; dioxidoisothiazolidinyl; phenyl,pyridyl, furyl, thienyl, C(═O)—NH-phenyl, NH—C(═O)-phenyl, NH(phenyl),C(═O)—NH-pyridyl, NH—C(═O)-pyridyl, NH(pyridyl), wherein phenyl,pyridyl, thienyl or furyl are respectively unsubstituted or mono- orpolysubstituted with one or more substituents selected independently ofone another from the group consisting of F, Cl, Br, I, CN, OH, O—C₁₋₄alkyl, OCF₃, C₁₋₄ alkyl, CF₃, SH, S—C₁₋₄ alkyl and SCF₃.

Particularly preferred are compounds according to the invention from thegroup

-   1    N-((3-tert-butyl-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(methylsulphonamido)phenyl)propanamide;-   2    (S)—N-((3-tert-butyl-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(methylsulphonamido)phenyl)propanamide;-   3    N-((3-tert-butyl-1-methyl-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(methylsulphonamido)phenyl)propanamide;-   4    (S)—N-((3-tert-butyl-1-methyl-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(methylsulphonamido)phenyl)propanamide;-   5    N-((3-tert-butyl-1-hexyl-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(methylsulphonamido)phenyl)propanamide;-   6    (S)—N-((3-tert-butyl-1-hexyl-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(methylsulphonamido)phenyl)propanamide;-   7    N-((3-tert-butyl-1-cyclohexyl-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(methylsulphonamido)phenyl)propanamide;-   8    (S)—N-((3-tert-butyl-1-cyclohexenyl-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(methylsulphonamido)phenyl)propanamide;-   9    2-(3-fluoro-4-(methylsulphonamido)phenyl)-N-((3-methyl-1-phenyl-1H-pyrazol-5-yl)methyl)propanamide;    N-((3-chloro-1-phenyl-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(methylsulphonamido)phenyl)propanamide;-   11    2-(3-fluoro-4-(methylsulphonamido)phenyl)-N-((3-(4-fluorophenyl)-1-phenyl-1H-pyrazol-5-yl)methyl)propanamide;-   12    N-((3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(methylsulphonamido)phenyl)propanamide;-   13    N-((3-tert-butyl-1-(4-tert-butylphenyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(methylsulphonamido)phenyl)propanamide;-   14    N-((3-tert-butyl-1-(4-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(methylsulphonamido)phenyl)propanamide;-   15    (S)—N-((3-tert-butyl-1-(4-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(methylsulphonamido)phenyl)propanamide;-   16    N-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(methylsulphonamido)phenyl)propanamide;-   17    (S)—N-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(methylsulphonamido)phenyl)propanamide;-   18    N-((3-tert-butyl-1-(3-chloro-4-fluorophenyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(methylsulphonamido)phenyl)propanamide;-   19    (E)-N-((3-tert-butyl-1-(4-methylstyryl)-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(methylsulphonamido)phenyl)propanamide;-   20    N-((3-tert-butyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(methylsulphonamido)phenyl)propanamide;-   21    N-((1-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(methylsulphonamido)phenyl)propanamide;-   22    (R)—N-((1-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(methylsulphonamido)phenyl)propanamide;-   23    (S)—N-((1-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(methylsulphonamido)phenyl)propanamide;-   24    N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(methylsulphonamido)phenyl)propanamide;-   25    (R)—N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(methylsulphonamido)phenyl)propanamide;-   26    (S)—N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(methylsulphonamido)phenyl)propanamide;-   27    N-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2-(3-methoxy-4-(methylsulphonamido)phenyl)propanamide;-   28    N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(3-methoxy-4-(methylsulphonamido)phenyl)propanamide;-   29    N-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2-(3,5-difluoro-4-(methylsulphonamido)phenyl)propanamide;-   30    N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(3,5-difluorophenyl)propanamide;-   31    2-(4-bromo-3-fluorophenyl)-N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)propanamide;-   32    N-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2-(4-isobutylphenyl)propanamide;-   33    N-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(methylsulphonamidomethyl)phenyl)propanamide;-   34    N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(furan-3-yl)phenyl)propanamide;-   35    N-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2-(2-fluorobiphenyl-4-yl)propanamide;-   36    N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(4-(1,2-dihydroxyethyl)-3-fluorophenyl)propanamide;-   37    4-(1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylamino)-1-oxopropan-2-yl)-2-fluorobenzamide;-   38    4-(1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylamino)-1-oxopropan-2-yl)-N-ethylbenzamide;-   39    4-(1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylamino)-1-oxopropan-2-yl)-2-fluoro-N-phenylbenzamide;-   40    4-(1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylamino)-1-oxopropan-2-yl)-N-(4-fluorophenyl)benzamide;-   41    4-(1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylamino)-1-oxopropan-2-yl)-N-(4-(trifluoromethyl)phenyl)benzamide;-   42    4-(1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylamino)-1-oxopropan-2-yl)-N-(pyridin-4-yl)benzamide;-   43    N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(4-(trifluormethoxy)phenyl)propanamide;-   44    N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(3,5-dibromo-4-hydroxyphenyl)acetamide;-   45    N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(3,5-dibromo-4-hydroxyphenyl)propanamide;-   46    N-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2-(3,5-difluoro-4-hydroxyphenyl)propanamide;-   47    N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(3,5-difluoro-4-methoxyphenyl)propanamide;-   48    N-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2-(4-methoxy-3,5-dimethylphenyl)acetamide;-   49    N-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2-(4-(N,N-dimethylsulphamoyl)-3-fluorophenyl)propanamide;-   50    N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(4-(4-chlorophenylamino)phenyl)propanamide;-   51    N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(4-(4-methoxyphenylamino)phenyl)propanamide;-   52    2-(4-amino-3,5-difluorophenyl)-N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)propanamide;-   53    2-(4-acetamido-3-fluorophenyl)-N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)propanamide;-   54    N-(4-(1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylamino)-1-oxopropan-2-yl)-2-fluorophenyl)benzamide;-   55    N-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2-[4-(1,1-dioxidoisothiazolidin-2-yl)-3-fluorophenyl]propanamide;-   56    N-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2-(4-(N,N-dimethylsulphamoyl)-3-fluorophenyl)propanamide;-   57    1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(3,5-difluorophenyl)urea;-   58    1-(4-bromo-3-fluorophenyl)-3-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)urea;-   59    1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(4-(trifluoromethyl)phenyl)urea;-   60    1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(4-(difluormethoxy)phenyl)urea;-   61    1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(3,5-difluoro-4-methoxyphenyl)urea;-   62    1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(4-methoxy-3,5-dimethylphenyl)urea;-   63    1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(3-fluoro-4-(methylsulphonyl)phenyl)urea;-   64    1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(4-(phenylamino)phenyl)urea;-   65    4-(3-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)ureido)-N-(4-fluorophenyl)benzamide;-   66    N-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(methylsulphonamido)phenyl)-2-(3-fluorophenyl)acetamide;-   67    N-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2-cyclohexyl-2-(3-fluoro-4-(methylsulphonamido)phenyl)acetamide;-   68    N-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(methylsulphonamido)phenyl)-2-p-tolylacetamide;-   69    N-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2-(3-chloro-4-(methylthio)phenyl)propanamide;-   70    N-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2-(3-chloro-4-(methylsulphonyl)phenyl)propanamide;-   71    N-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(methylthio)phenyl)propanamide;-   72    N-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(methylsulphonyl)phenyl)propanamide;-   73    N-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluorophenyl)acetamide;-   74    N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluorophenyl)acetamide;-   75    N-[[5-tert-butyl-2-(3-chlorophenyl)-2H-[1,2,4]triazol-3-yl]-methyl]-2-[3-fluoro-4-(methanesulphonamido)phenyl]propionamide;-   76    N-[[2-(3-chlorophenyl)-5-(trifluoromethyl)-2H-[1,2,4]triazol-3-yl]-methyl]-2-[3-fluoro-4-(methanesulphonamido)phenyl]propionamide;-   77    N-[(5-tert-butyl-2-cyclohexyl-2H-[1,2,4]triazol-3-yl)-methyl]-2-[3-fluoro-4-(methanesulphonamido)phenyl]propionamide;-   78    N-[[2-cyclohexyl-5-(trifluoromethyl)-2H-[1,2,4]triazol-3-yl]-methyl]-2-[3-fluoro-4-(methanesulphonamido)phenyl]propionamide;-   79    N-[(5-tert-butyl-2-pyridin-3-yl-2H-[1,2,4]triazol-3-yl)-methyl]-2-[3-fluoro-4-(methanesulphonamido)phenyl]propionamide;-   80    2-[3-fluoro-4-(methanesulphonamido)phenyl]-N-[[2-pyridin-3-yl-5-(trifluoromethyl)-2H-[1,2,4]triazol-3-yl]-methyl]propionamide;-   81    N-[[5-tert-butyl-2-(6-chloropyridin-2-yl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(methanesulphonamido)phenyl]propionamide;-   82    N-[[5-tert-butyl-2-(3,3-difluorocyclobutanecarbonyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(methanesulphonamido)phenyl]propionamide;-   83    N-[[2-(3-chlorophenyl)-4-methyl-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(methanesulphonamido)phenyl]propionamide;-   84    N-[[2-(dipropylamino)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[4-(methanesulphonamido)-3-methoxyphenyl]propionamide;-   85    N-[[2-(dipropylamino)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(hydroxymethyl)phenyl]propionamide;-   86    N-[[2-(dipropylamino)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(methanesulphonamido)phenyl]propionamide;-   87    N-[[2-(dipropylamino)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-(3-fluorophenyl)acetamide;-   88    4-[1-[[2-(dipropylamino)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methylcarbamoyl]ethyl]-2-fluorobenzamide;-   89    4-[1-[[2-(dipropylamino)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methylcarbamoyl]ethyl]-N-pyridin-2-yl-benzamide;-   90    2-[3-fluoro-4-(hydroxymethyl)phenyl]-N-[[2-piperidin-1-yl-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]propionamide;-   91    2-[3-fluoro-4-(2-hydroxyethyl)phenyl]-N-[[2-piperidin-1-yl-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]propionamide;-   92    2-[3-fluoro-4-(methanesulphonamido)phenyl]-N-[[2-piperidin-1-yl-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]propionamide;-   93    2-[4-(methanesulphonamido)-3-methoxyphenyl]-N-[[2-piperidin-1-yl-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]propionamide;-   94    2-[4-(1,2-dihydroxyethyl)-3-fluorophenyl]-N-[[2-piperidin-1-yl-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]propionamide;-   95    2-(3-fluorophenyl)-N-[[2-piperidin-1-yl-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]acetamide;-   96    2-fluoro-4-[1-[[2-piperidin-1-yl-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methylcarbamoyl]ethyl]benzamide;-   97    2-[3-fluoro-4-(methanesulphonamido)phenyl]-N-[[2-[(4-fluorophenyl)methylmethylamino]-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]propionamide;-   98    N-[[5-tert-butyl-2-(2,2,2-trifluoroethylamino)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(methanesulphonamido)phenyl]propionamide;-   99    N-[[2-butoxy-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(hydroxymethyl)phenyl]propionamide;-   100    N-[[2-butoxy-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(methanesulphonamido)phenyl]propionamide;-   101    N-[[2-butoxy-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[4-(methanesulphonamido)-3-methoxyphenyl]propionamide;-   102    N-[(2-butoxy-5-tert-butyl-2H-pyrazol-3-yl)-methyl]-2-(3-fluorophenyl)acetamide;-   103    N-[[2-cyclopentyloxy-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(methanesulphonamido)phenyl]propionamide;-   104    N-[[2-cyclopentyloxy-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[4-(methanesulphonamido)-3-methoxyphenyl]propionamide;-   105    2-(3-fluorophenyl)-N-[[2-[(4-methoxyphenyl)methoxy]-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]acetamide;-   106    N-[[5-tert-butyl-2-(3-cyano-5-fluorophenoxy)-2H-pyrazol-3-yl]-methyl]-2-(3-fluorophenyl)acetamide;-   107    N-[[2-(cyclohexylsulphanyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(methanesulphonamido)phenyl]propionamide;-   108    N-[[2-(benzenesulphonyl)-5-tert-butyl-2H-pyrazol-3-yl]-methyl]-2-(3-fluorophenyl)acetamide;-   109    N-[[2-cyclohexyl-5-(trifluoromethyl)-2H-[1,2,4]triazol-3-yl]-methyl]-2-[4-(methanesulphonamido)-3-methoxyphenyl]propionamide;-   110    N-[[2-cyclohexyl-5-(trifluoromethyl)-2H-[1,2,4]triazol-3-yl]-methyl]-2-(3-fluorophenyl)acetamide;-   111    4-[1-[[2-cyclohexyl-5-(trifluoromethyl)-2H-[1,2,4]triazol-3-yl]-methylcarbamoyl]ethyl]-2-fluorobenzamide;-   112    2-[3-fluoro-4-(hydroxymethyl)phenyl]-N-[[2-hexyl-5-(trifluoromethyl)-2H-[1,2,4]triazol-3-yl]-methyl]propionamide;-   113    4-[1-[[2-cyclobutyl-5-(trifluoromethyl)-2H-[1,2,4]triazol-3-yl]-methylcarbamoyl]ethyl]-2-fluorobenzamide;-   114    N-[[5-tert-butyl-2-(3,3-difluorocyclobutanecarbonyl)-2H-[1,2,4]triazol-3-yl]-methyl]-2-[3-fluoro-4-(methanesulphonamido)phenyl]propionamide;-   115    N-[[5-tert-butyl-2-(3-cyano-5-fluorophenoxy)-2H-[1,2,4]triazol-3-yl]-methyl]-2-(3-fluorophenyl)acetamide;-   116    N-[[2-(benzenesulphonyl)-5-tert-butyl-2H-[1,2,4]triazol-3-yl]-methyl]-2-(3-fluorophenyl)acetamide;-   117    N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluorophenyl)-2-methylpropanamide;-   118    N-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-1-(3-fluorophenyl)cyclopropancarboxamide;-   119    N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-1-(3-fluorophenyl)cyclobutancarboxamide;-   120    N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-1-(3-fluorophenyl)cyclopentancarboxamide;-   121    N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-1-(3-fluorophenyl)cyclohexancarboxamide;-   122    1-((3-tert-butyl-1-(4-fluorophenyl)-1H-pyrazol-5-yl)methyl)-3-(3-fluorophenyl)urea-   123    3-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-1-(3-fluorophenyl)-1-methylurea;-   124    N-((1-(3-chloro-4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(methylsulfonylmethyl)phenyl)propanamide;-   125    N-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2-(4-cyclopropyl-3-fluorophenyl)propanamide;-   126    1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(4-cyclopropyl-3-fluorophenyl)urea;-   127    N-((3-tert-butyl-1-(pyridin-2-yl)-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(methylsulfonamidmethyl)phenyl)propanamide;-   128    N-((1-(3-chlorophenyl)-3-cyclopropyl-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(methylsulfonylmethyl)phenyl)propanamide;-   129    2-(3-fluoro-4-(methylsulfonamidmethyl)phenyl)-N-((1-(pyridin-2-ylmethylamino)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)propanamide;-   130    N-((1-(3-chlorophenyl)-4-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluorophenyl)acetamide;-   131    2-(3-fluorophenyl)-N-((1-pentyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)acetamide;-   132    2-(3-fluorophenyl)-N-((1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)acetamide;-   133    N-((3-tert-butyl-1-(2,2,2-trifluoroethylamino)-1H-pyrazol-5-yl)methyl)-2-(3-fluorophenyl)acetamide;-   134    N-((1-(3-chlorophenyl)-4-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(methylsulfonamidmethyl)phenyl)propanamide;-   135    N-((3-tert-butyl-1-(3-chlorophenyl)-1H-1,2,4-triazol-5-yl)methyl)-2-(3-fluorophenyl)acetamide;-   136    2-(3-fluorophenyl)-N-((1-(pyridin-3-yl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)acetamide;-   137    N-((1-cyclohexyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(methylsulfonamidmethyl)phenyl)propanamide;-   138    2-(3-fluoro-4-(methylsulfonamidmethyl)phenyl)-N-((1-(tetrahydro-2H-pyran-4-yl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)propanamide;-   139    1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(4-(cyclopropylethynyl)-3-fluorophenyl)urea;-   140    N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(trifluoromethyl)phenyl)acetamide;-   141    N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(trifluoromethyl)phenyl)propanamide;-   142    N-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-((2-methoxyethoxy)methyl)phenyl)propanamide;-   143    4-(1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylamino)-1-oxopropan-2-yl)-N-phenylbenzamide;-   144    1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(3-fluoro-4-morpholinphenyl)urea;-   145    N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(methylsulfonamid)phenyl)-3-phenylpropanamide;-   146    N-(5-((2-(3-fluorophenyl)acetamide)methyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzamide;-   147    N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(3,5-difluoro-4-hydroxyphenyl)acetamide;

respectively in the form of the free compounds; the racemate; theenantiomers, diastereomers, mixtures of the enantiomers or diastereomersor of an individual enantiomer or diastereomer; or in the form of thesalts of physiologically compatible acids or bases; or in the form ofsolvates.

Furthermore, preference may be given to compounds according to theinvention of general formula (I) that cause a 50 percent displacement ofcapsaicin, which is present at a concentration of 100 nM, in a FLIPRassay with CHO K1 cells which were transfected with the human VR1 geneat a concentration of less than 2,000 nM, preferably less than 1,000 nM,particularly preferably less than 300 nM, most particularly preferablyless than 100 nM, even more preferably less than 75 nM, additionallypreferably less than 50 nM, most preferably less than 10 nM.

In the process, the Ca²⁺ influx is quantified in the FLIPR assay withthe aid of a Ca²⁺-sensitive dye (type Fluo-4, Molecular Probes EuropeBV, Leiden, the Netherlands) in a fluorescent imaging plate reader(FLIPR, Molecular Devices, Sunnyvale, USA), as described hereinafter.

The present invention further relates to a process for preparingcompounds of the above-indicated general formula (I), according to whichat least one compound of general formula (II),

in which X, R¹, R², R⁴ and n have one of the foregoing meanings, isreacted in a reaction medium, if appropriate in the presence of at leastone suitable coupling reagent, if appropriate in the presence of atleast one base, with a compound of general formula (III) or (IV),

in which Hal represents a halogen, preferably Cl or Br, and R^(5a),R^(5b), R⁶, R⁷, R⁸, R⁹ and R¹⁰ each have one of the foregoing meanings,in a reaction medium, if appropriate in the presence of at least onesuitable coupling reagent, if appropriate in the presence of at leastone base, to form a compound of general formula (I),

in which A represents CR^(5b) and X, R¹, R², R⁴, R^(5a), R^(5b), R⁶, R⁷,R⁸, R⁹, R¹⁰ and n have one of the foregoing meanings;

or in that at least one compound of general formula (II),

in which X, R¹, R², R⁴ and n have one of the foregoing meanings, isreacted to form a compound of general formula (V)

in which X, R¹, R², R⁴ and n have one of the foregoing meanings, in areaction medium, in the presence of phenyl chloroformate, if appropriatein the presence of at least one base and/or a coupling reagent, and saidcompound is if appropriate purified and/or isolated, and a compound ofgeneral formula (V) is reacted with a compound of general formula (VI),

in which R⁶, R⁷, R⁸, R⁹ and R¹⁰ have one of the foregoing meanings, in areaction medium, if appropriate in the presence of at least one suitablecoupling reagent, if appropriate in the presence of at least one base,to form a compound of general formula (I),

in which A represents N and X, R¹, R², R⁴, R^(5a), R⁶, R⁷, R⁸ R⁹ and R¹⁰and n have one of the foregoing meanings.

The reaction of compounds of the above-indicated general formulae (II)and (VI) with carboxylic acids of the above-indicated general formula(III) to form compounds of the above-indicated general formula (I) iscarried out preferably in a reaction medium selected from the groupconsisting of diethyl ether, tetrahydrofuran, acetonitrile, methanol,ethanol, (1,2)-dichloroethane, dimethylformamide, dichloromethane andcorresponding mixtures, if appropriate in the presence of at least onecoupling reagent, preferably selected from the group consisting of1-benzotriazolyloxy-tris-(dimethylamino)-phosphonium hexafluorophosphate(BOP), dicyclohexylcarbodiimide (DCC),N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide (EDCI),diisopropylcarbodiimide, 1,1′-carbonyldiimidazole (CDI),N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridino-1-yl-methylene]-N-methylmethanaminiumhexafluorophosphate N-oxide (HATU),O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (TBTU), N-hydroxybenzotriazole (HOBt) and1-hydroxy-7-azabenzotriazole (HOAt), if appropriate in the presence ofat least one organic base, preferably selected from the group consistingof triethylamine, pyridine, dimethylaminopyridine, N-methylmorpholineand diisopropylethylamine, preferably at temperatures of from −70° C. to100° C.

Alternatively, the reaction of compounds of the above-indicated generalformulae (II) and (VI) with carboxylic acid halides of theabove-indicated general formula (IV), in which Hal represents a halogenas the leaving group, preferably a chlorine or bromine atom, to formcompounds of the above-indicated general formula (I) is carried out in areaction medium preferably selected from the group consisting of diethylether, tetrahydrofuran, acetonitrile, methanol, ethanol,dimethylformamide, dichloromethane and corresponding mixtures, ifappropriate in the presence of an organic or inorganic base, preferablyselected from the group consisting of triethylamine,dimethylaminopyridine, pyridine and diisopropylamine, at temperatures offrom −70° C. to 100° C.

The compounds of the above-indicated formulae (II), (III), (IV), (V) and(VI) are each commercially available and/or can be prepared usingconventional processes known to the person skilled in the art.

The reactions described hereinbefore can each be carried out under theconventional conditions with which the person skilled in the art isfamiliar, for example with regard to pressure or the order in which thecomponents are added. If appropriate, the person skilled in the art candetermine the optimum procedure under the respective conditions bycarrying out simple preliminary tests. The intermediate and end productsobtained using the reactions described hereinbefore can each be purifiedand/or isolated, if desired and/or required, using conventional methodsknown to the person skilled in the art. Suitable purifying processes arefor example extraction processes and chromatographic processes such ascolumn chromatography or preparative chromatography. All of the processsteps described hereinbefore, as well as the respective purificationand/or isolation of intermediate or end products, can be carried outpartly or completely under an inert gas atmosphere, preferably under anitrogen atmosphere.

The substituted compounds according to the invention of theaforementioned general formula (I) and also corresponding stereoisomerscan be isolated both in the form of their free bases, their free acidsand also in the form of corresponding salts, in particularphysiologically compatible salts.

The free bases of the respective substituted compounds according to theinvention of the aforementioned general formula (I) and also ofcorresponding stereoisomers can be converted into the correspondingsalts, preferably physiologically compatible salts, for example byreaction with an inorganic or organic acid, preferably with hydrochloricacid, hydrobromic acid, sulphuric acid, methanesulphonic acid,p-toluenesulphonic acid, carbonic acid, formic acid, acetic acid, oxalicacid, succinic acid, tartaric acid, mandelic acid, fumaric acid, maleicacid, lactic acid, citric acid, glutamic acid, saccharic acid,monomethylsebacic acid, 5-oxoproline, hexane-1-sulphonic acid, nicotinicacid, 2, 3 or 4-aminobenzoic acid, 2,4,6-trimethylbenzoic acid, α-lipoicacid, acetyl glycine, hippuric acid, phosphoric acid and/or asparticacid. The free bases of the respective substituted compounds of theaforementioned general formula (I) and of corresponding stereoisomerscan likewise be converted into the corresponding physiologicallycompatible salts using the free acid or a salt of a sugar additive, suchas for example saccharin, cyclamate or acesulphame.

Accordingly, the free acids of the substituted compounds of theaforementioned general formula (I) and of corresponding stereoisomerscan be converted into the corresponding physiologically compatible saltsby reaction with a suitable base. Examples include the alkali metalsalts, alkaline earth metals salts or ammonium salts [NH_(x)R_(4-x)]⁺,in which x=0, 1, 2, 3 or 4 and R represents a branched or unbranchedC₁₋₄ alkyl residue.

The substituted compounds according to the invention of theaforementioned general formula (I) and of corresponding stereoisomerscan if appropriate, like the corresponding acids, the correspondingbases or salts of these compounds, also be obtained in the form of theirsolvates, preferably in the form of their hydrates, using conventionalmethods known to the person skilled in the art.

If the substituted compounds according to the invention of theaforementioned general formula (I) are obtained, after preparationthereof, in the form of a mixture of their stereoisomers, preferably inthe form of their racemates or other mixtures of their variousenantiomers and/or diastereomers, they can be separated and ifappropriate isolated using conventional processes known to the personskilled in the art. Examples include chromatographic separatingprocesses, in particular liquid chromatography processes under normalpressure or under elevated pressure, preferably MPLC and HPLC processes,and also fractional crystallisation processes. These processes allowindividual enantiomers, for example diastereomeric salts formed by meansof chiral stationary phase HPLC or by means of crystallisation withchiral acids, for example (+)-tartaric acid, (−)-tartaric acid or(+)-10-camphorsulphonic acid, to be separated from one another.

The substituted compounds according to the invention of theaforementioned general formula (I) and corresponding stereoisomers andalso the respective corresponding acids, bases, salts and solvates aretoxicologically safe and are therefore suitable as pharmaceutical activeingredients in pharmaceutical compositions.

The present invention therefore further relates to a pharmaceuticalcomposition containing at least one compound according to the inventionof the above-indicated formula (I), in each case if appropriate in theform of one of its pure stereoisomers, in particular enantiomers ordiastereomers, its racemates or in the form of a mixture ofstereoisomers, in particular the enantiomers and/or diastereomers, inany desired mixing ratio, or respectively in the form of a correspondingsalt, or respectively in the form of a corresponding solvate, and alsoif appropriate one or more pharmaceutically compatible auxiliaries.

These pharmaceutical compositions according to the invention aresuitable in particular for vanilloid receptor 1-(VR1/TRPV1) regulation,preferably for vanilloid receptor 1-(VR1/TRPV1) inhibition and/or forvanilloid receptor 1-(VR1/TRPV1) stimulation, i.e. they exert anagonistic or antagonistic effect.

Likewise, the pharmaceutical compositions according to the invention arepreferably suitable for the prophylaxis and/or treatment of disorders ordiseases which are mediated, at least in some cases, by vanilloidreceptors 1.

The pharmaceutical composition according to the invention is suitablefor administration to adults and children, including toddlers andbabies.

The pharmaceutical composition according to the invention may be foundas a liquid, semisolid or solid pharmaceutical form, for example in theform of injection solutions, drops, juices, syrups, sprays, suspensions,tablets, patches, capsules, plasters, suppositories, ointments, creams,lotions, gels, emulsions, aerosols or in multiparticulate form, forexample in the form of pellets or granules, if appropriate pressed intotablets, decanted in capsules or suspended in a liquid, and also beadministered as much.

In addition to at least one substituted compound of the above-indicatedformula (I), if appropriate in the form of one of its purestereoisomers, in particular enantiomers or diastereomers, its racemateor in the form of mixtures of the stereoisomers, in particular theenantiomers or diastereomers, in any desired mixing ratio, or ifappropriate in the form of a corresponding salt or respectively in theform of a corresponding solvate, the pharmaceutical compositionaccording to the invention conventionally contains furtherphysiologically compatible pharmaceutical auxiliaries which can forexample be selected from the group consisting of excipients, fillers,solvents, diluents, surface-active substances, dyes, preservatives,blasting agents, slip additives, lubricants, aromas and binders.

The selection of the physiologically compatible auxiliaries and also theamounts thereof to be used depend on whether the pharmaceuticalcomposition is to be applied orally, subcutaneously, parenterally,intravenously, intraperitoneally, intradermally, intramuscularly,intranasally, buccally, rectally or locally, for example to infectionsof the skin, the mucous membranes and of the eyes. Preparations in theform of tablets, dragees, capsules, granules, pellets, drops, juices andsyrups are preferably suitable for oral application; solutions,suspensions, easily reconstitutable dry preparations and also sprays arepreferably suitable for parenteral, topical and inhalative application.The substituted compounds according to the invention used in thepharmaceutical composition according to the invention in a repository indissolved form or in a plaster, agents promoting skin penetration beingadded if appropriate, are suitable percutaneous applicationpreparations. Orally or percutaneously applicable preparation forms canrelease the respective substituted compound according to the inventionalso in a delayed manner.

The pharmaceutical compositions according to the invention are preparedwith the aid of conventional means, devices, methods and process knownin the art, such as are described for example in “Remington'sPharmaceutical Sciences”, A. R. Gennaro (Editor), 17^(th) edition, MackPublishing Company, Easton, Pa., 1985, in particular in Part 8, Chapters76 to 93. The corresponding description is introduced herewith by way ofreference and forms part of the disclosure. The amount to beadministered to the patient of the respective substituted compoundsaccording to the invention of the above-indicated general formula I mayvary and is for example dependent on the patient's weight or age andalso on the type of application, the indication and the severity of thedisorder. Conventionally 0.001 to 100 mg/kg, preferably 0.05 to 75mg/kg, particularly preferably 0.05 to 50 mg of at least one suchcompound according to the invention are applied per kg of the patient'sbody weight.

The pharmaceutical composition according to the invention is preferablysuitable for the treatment and/or prophylaxis of one or more disordersselected from the group consisting of pain selected from the groupconsisting of acute pain, chronic pain, neuropathic pain and visceralpain; joint pain; hyperalgesia; allodynia; causalgia; migraine;depression; nervous affection; axonal injuries; neurodegenerativediseases, preferably selected from the group consisting of multiplesclerosis, Alzheimer's disease, Parkinson's disease and Huntington'sdisease; cognitive dysfunctions, preferably cognitive deficiency states,particularly preferably memory disorders; epilepsy; respiratorydiseases, preferably selected from the group consisting of asthma,bronchitis and pulmonary inflammation; coughs; urinary incontinence;overactive bladder (OAB); disorders and/or injuries of thegastrointestinal tract; duodenal ulcers; gastric ulcers; irritable bowelsyndrome; strokes; eye irritations; skin irritations; neurotic skindiseases; allergic skin diseases; psoriasis; vitiligo; herpes simplex;inflammations, preferably inflammations of the intestine, the eyes, thebladder, the skin or the nasal mucous membrane; diarrhoea; pruritus;osteoporosis; arthritis; osteoarthritis; rheumatic diseases; eatingdisorders, preferably selected from the group consisting of bulimia,cachexia, anorexia and obesity; medication dependency; misuse ofmedication; withdrawal symptoms in medication dependency; development oftolerance to medication, preferably to natural or synthetic opioids;drug dependency; misuse of drugs; withdrawal symptoms in drugdependency; alcohol dependency; misuse of alcohol and withdrawalsymptoms in alcohol dependency; for diuresis; for antinatriuresis; forinfluencing the cardiovascular system; for increasing vigilance; for thetreatment of wounds and/or burns; for the treatment of severed nerves;for increasing libido; for modulating movement activity; for anxiolysis;for local anaesthesia and/or for inhibiting undesirable side effects,preferably selected from the group consisting of hyperthermia,hypertension and bronchoconstriction, triggered by the administration ofvanilloid receptor 1 (VR1/TRPV1 receptor) agonists, preferably selectedfrom the group consisting of capsaicin, resiniferatoxin, olvanil,arvanil, SDZ-249665, SDZ-249482, nuvanil and capsavanil.

Particularly preferably, the pharmaceutical composition according to theinvention is suitable for the treatment and/or prophylaxis of one ormore disorders selected from the group consisting of pain, preferably ofpain selected from the group consisting of acute pain, chronic pain,neuropathic pain and visceral pain; joint pain; migraine; depression;neurodegenerative diseases, preferably selected from the groupconsisting of multiple sclerosis, Alzheimer's disease, Parkinson'sdisease and Huntington's disease; cognitive dysfunctions, preferablycognitive deficiency states, particularly preferably memory disorders;inflammations, preferably inflammations of the intestine, the eyes, thebladder, the skin or the nasal mucous membrane; urinary incontinence;overactive bladder (OAB); medication dependency; misuse of medication;withdrawal symptoms in medication dependency; development of toleranceto medication, preferably development of tolerance to natural orsynthetic opioids; drug dependency; misuse of drugs; withdrawal symptomsin drug dependency; alcohol dependency; misuse of alcohol and withdrawalsymptoms in alcohol dependency.

Most particularly preferably, the pharmaceutical composition accordingto the invention is suitable for the treatment and/or prophylaxis ofpain, preferably of pain selected from the group consisting of acutepain, chronic pain, neuropathic pain and visceral pain, and/or urinaryincontinence.

The present invention further relates to the use of at least onecompound according to the invention and also if appropriate of one ormore pharmaceutically compatible auxiliaries for the preparation of apharmaceutical composition for vanilloid receptor 1-(VR1/TRPV1)regulation, preferably for vanilloid receptor 1-(VR1/TRPV1) inhibitionand/or for vanilloid receptor 1-(VR1/TRPV1) stimulation.

Preference is given to the use of at least one substituted compoundaccording to the invention and also if appropriate of one or morepharmaceutically compatible auxiliaries for the preparation of apharmaceutical composition for the prophylaxis and/or treatment ofdisorders or diseases which are mediated, at least in some cases, byvanilloid receptors 1.

Particular preference is given to the use of at least one compoundaccording to the invention and also if appropriate of one or morepharmaceutically compatible auxiliaries for the preparation of apharmaceutical composition for the treatment and/or prophylaxis of oneor more disorders selected from the group consisting of pain, preferablyof pain selected from the group consisting of acute pain, chronic pain,neuropathic pain and visceral pain and joint pain.

Particular preference is given to the use of at least one compoundaccording to the invention and also if appropriate of one or morepharmaceutically compatible auxiliaries for the preparation of apharmaceutical composition for the treatment and/or prophylaxis of oneor more disorders selected from the group consisting of hyperalgesia;allodynia; causalgia; migraine; depression; nervous affection; axonalinjuries; neurodegenerative diseases, preferably selected from the groupconsisting of multiple sclerosis, Alzheimer's disease, Parkinson'sdisease and Huntington's disease; cognitive dysfunctions, preferablycognitive deficiency states, particularly preferably memory disorders;epilepsy; respiratory diseases, preferably selected from the groupconsisting of asthma, bronchitis and pulmonary inflammation; coughs;urinary incontinence; overactive bladder (OAB); disorders and/orinjuries of the gastrointestinal tract; duodenal ulcers; gastric ulcers;irritable bowel syndrome; strokes; eye irritations; skin irritations;neurotic skin diseases; allergic skin diseases; psoriasis; vitiligo;herpes simplex; inflammations, preferably inflammations of theintestine, the eyes, the bladder, the skin or the nasal mucous membrane;diarrhoea; pruritus; osteoporosis; arthritis; osteoarthritis; rheumaticdiseases; eating disorders, preferably selected from the groupconsisting of bulimia, cachexia, anorexia and obesity; medicationdependency; misuse of medication; withdrawal symptoms in medicationdependency; development of tolerance to medication, preferably tonatural or synthetic opioids; drug dependency; misuse of drugs;withdrawal symptoms in drug dependency; alcohol dependency; misuse ofalcohol and withdrawal symptoms in alcohol dependency; for diuresis; forantinatriuresis; for influencing the cardiovascular system; forincreasing vigilance; for the treatment of wounds and/or burns; for thetreatment of severed nerves; for increasing libido; for modulatingmovement activity; for anxiolysis; for local anaesthesia and/or forinhibiting undesirable side effects, preferably selected from the groupconsisting of hyperthermia, hypertension and bronchoconstriction,triggered by the administration of vanilloid receptor 1 (VR1/TRPV1receptor) agonists, preferably selected from the group consisting ofcapsaicin, resiniferatoxin, olvanil, arvanil, SDZ-249665, SDZ-249482,nuvanil and capsavanil.

Most particular preference is given to the use of at least onesubstituted compound according to the invention and also if appropriateof one or more pharmaceutically compatible auxiliaries for thepreparation of a pharmaceutical composition for the treatment and/orprophylaxis of one or more disorders selected from the group consistingof pain, preferably of pain selected from the group consisting of acutepain, chronic pain, neuropathic pain and visceral pain; joint pain;migraine; depression; neurodegenerative diseases, preferably selectedfrom the group consisting of multiple sclerosis, Alzheimer's disease,Parkinson's disease and Huntington's disease; cognitive dysfunctions,preferably cognitive deficiency states, particularly preferably memorydisorders; inflammations, preferably inflammations of the intestine, theeyes, the bladder, the skin or the nasal mucous membrane; urinaryincontinence; overactive bladder (OAB); medication dependency; misuse ofmedication; withdrawal symptoms in medication dependency; development oftolerance to medication, preferably development of tolerance to naturalor synthetic opioids; drug dependency; misuse of drugs; withdrawalsymptoms in drug dependency; alcohol dependency; misuse of alcohol andwithdrawal symptoms in alcohol dependency.

Particular preference is given to the use of at least one substitutedcompound according to the invention and also if appropriate of one ormore pharmaceutically compatible auxiliaries for the preparation of apharmaceutical composition for the treatment and/or prophylaxis of pain,preferably selected from the group consisting of acute pain, chronicpain, neuropathic pain and visceral pain, and/or urinary incontinence.

The present invention further relates to at least one substitutedcompound according to the invention and also if appropriate to one ormore pharmaceutically compatible auxiliaries for vanilloid receptor1-(VR1/TRPV1) regulation, preferably for vanilloid receptor1-(VR1/TRPV1) inhibition and/or for vanilloid receptor 1-(VR1/TRPV1)stimulation.

Preference is given to at least one substituted compound according tothe invention and also if appropriate to one or more pharmaceuticallycompatible auxiliaries for the prophylaxis and/or treatment of disordersor diseases which are mediated, at least in some cases, by vanilloidreceptors 1.

Particular preference is given to at least one compound according to theinvention and also if appropriate to one or more pharmaceuticallycompatible auxiliaries for the treatment and/or prophylaxis of one ormore disorders selected from the group consisting of pain, preferably ofpain selected from the group consisting of acute pain, chronic pain,neuropathic pain and visceral pain and joint pain.

Particular preference is given to at least one compound according to theinvention and also if appropriate to one or more pharmaceuticallycompatible auxiliaries for the treatment and/or prophylaxis of one ormore disorders selected from the group consisting of hyperalgesia;allodynia; causalgia; migraine; depression; nervous affection; axonalinjuries; neurodegenerative diseases, preferably selected from the groupconsisting of multiple sclerosis, Alzheimer's disease, Parkinson'sdisease and Huntington's disease; cognitive dysfunctions, preferablycognitive deficiency states, particularly preferably memory disorders;epilepsy; respiratory diseases, preferably selected from the groupconsisting of asthma, bronchitis and pulmonary inflammation; coughs;urinary incontinence; overactive bladder (OAB); disorders and/orinjuries of the gastrointestinal tract; duodenal ulcers; gastric ulcers;irritable bowel syndrome; strokes; eye irritations; skin irritations;neurotic skin diseases; allergic skin diseases; psoriasis; vitiligo;herpes simplex; inflammations, preferably inflammations of theintestine, the eyes, the bladder, the skin or the nasal mucous membrane;diarrhoea; pruritus; osteoporosis; arthritis; osteoarthritis; rheumaticdiseases; eating disorders, preferably selected from the groupconsisting of bulimia, cachexia, anorexia and obesity; medicationdependency; misuse of medication; withdrawal symptoms in medicationdependency; development of tolerance to medication, preferably tonatural or synthetic opioids; drug dependency; misuse of drugs;withdrawal symptoms in drug dependency; alcohol dependency; misuse ofalcohol and withdrawal symptoms in alcohol dependency; for diuresis; forantinatriuresis; for influencing the cardiovascular system; forincreasing vigilance; for the treatment of wounds and/or burns; for thetreatment of severed nerves; for increasing libido; for modulatingmovement activity; for anxiolysis; for local anaesthesia and/or forinhibiting undesirable side effects, preferably selected from the groupconsisting of hyperthermia, hypertension and bronchoconstriction,triggered by the administration of vanilloid receptor 1 (VR1/TRPV1receptor) agonists, preferably selected from the group consisting ofcapsaicin, resiniferatoxin, olvanil, arvanil, SDZ-249665, SDZ-249482,nuvanil and capsavanil.

Most particular preference is given to at least one compound accordingto the invention and also if appropriate to one or more pharmaceuticallycompatible auxiliaries for the treatment and/or prophylaxis of one ormore disorders selected from the group consisting of pain, preferably ofpain selected from the group consisting of acute pain, chronic pain,neuropathic pain and visceral pain; joint pain; migraine; depression;neurodegenerative diseases, preferably selected from the groupconsisting of multiple sclerosis, Alzheimer's disease, Parkinson'sdisease and Huntington's disease; cognitive dysfunctions, preferablycognitive deficiency states, particularly preferably memory disorders;inflammations, preferably inflammations of the intestine, the eyes, thebladder, the skin or the nasal mucous membrane; urinary incontinence;overactive bladder (OAB); medication dependency; misuse of medication;withdrawal symptoms in medication dependency; development of toleranceto medication, preferably development of tolerance to natural orsynthetic opioids; drug dependency; misuse of drugs; withdrawal symptomsin drug dependency; alcohol dependency; misuse of alcohol and withdrawalsymptoms in alcohol dependency.

Particular preference is given to at least one compound according to theinvention and also if appropriate to one or more pharmaceuticallycompatible auxiliaries for the treatment and/or prophylaxis of pain,preferably selected from the group consisting of acute pain, chronicpain, neuropathic pain and visceral pain, and/or urinary incontinence.

The present invention further relates to at least one substitutedcompound according to the invention and also if appropriate to one ormore pharmaceutically compatible auxiliaries for use in vanilloidreceptor 1-(VR1/TRPV1) regulation, preferably for use in vanilloidreceptor 1-(VR1/TRPV1) inhibition and/or for vanilloid receptor1-(VR1/TRPV1) stimulation.

Preference is given to at least one substituted compound according tothe invention and also if appropriate to one or more pharmaceuticallycompatible auxiliaries for use in the prophylaxis and/or treatment ofdisorders or diseases which are mediated, at least in some cases, byvanilloid receptors 1.

Particular preference is given to at least one compound according to theinvention and also if appropriate to one or more pharmaceuticallycompatible auxiliaries for use in the treatment and/or prophylaxis ofone or more disorders selected from the group consisting of pain,preferably of pain selected from the group consisting of acute pain,chronic pain, neuropathic pain and visceral pain and joint pain.

Particular preference is given to at least one compound according to theinvention and also if appropriate to one or more pharmaceuticallycompatible auxiliaries for use in the treatment and/or prophylaxis ofone or more disorders selected from the group consisting ofhyperalgesia; allodynia; causalgia; migraine; depression; nervousaffection; axonal injuries; neurodegenerative diseases, preferablyselected from the group consisting of multiple sclerosis, Alzheimer'sdisease, Parkinson's disease and Huntington's disease; cognitivedysfunctions, preferably cognitive deficiency states, particularlypreferably memory disorders; epilepsy; respiratory diseases, preferablyselected from the group consisting of asthma, bronchitis and pulmonaryinflammation; coughs; urinary incontinence; overactive bladder (OAB);disorders and/or injuries of the gastrointestinal tract; duodenalulcers; gastric ulcers; irritable bowel syndrome; strokes; eyeirritations; skin irritations; neurotic skin diseases; allergic skindiseases; psoriasis; vitiligo; herpes simplex; inflammations, preferablyinflammations of the intestine, the eyes, the bladder, the skin or thenasal mucous membrane; diarrhoea; pruritus; osteoporosis; arthritis;osteoarthritis; rheumatic diseases; eating disorders, preferablyselected from the group consisting of bulimia, cachexia, anorexia andobesity; medication dependency; misuse of medication; withdrawalsymptoms in medication dependency; development of tolerance tomedication, preferably to natural or synthetic opioids; drug dependency;misuse of drugs; withdrawal symptoms in drug dependency; alcoholdependency; misuse of alcohol and withdrawal symptoms in alcoholdependency; for diuresis; for antinatriuresis; for influencing thecardiovascular system; for increasing vigilance; for the treatment ofwounds and/or burns; for the treatment of severed nerves; for increasinglibido; for modulating movement activity; for anxiolysis; for localanaesthesia and/or for inhibiting undesirable side effects, preferablyselected from the group consisting of hyperthermia, hypertension andbronchoconstriction, triggered by the administration of vanilloidreceptor 1 (VR1/TRPV1 receptor) agonists, preferably selected from thegroup consisting of capsaicin, resiniferatoxin, olvanil, arvanil,SDZ-249665, SDZ-249482, nuvanil and capsavanil.

Most particular preference is given to at least one compound accordingto the invention and also if appropriate to one or more pharmaceuticallycompatible auxiliaries for use in the treatment and/or prophylaxis ofone or more disorders selected from the group consisting of pain,preferably of pain selected from the group consisting of acute pain,chronic pain, neuropathic pain and visceral pain; joint pain; migraine;depression; neurodegenerative diseases, preferably selected from thegroup consisting of multiple sclerosis, Alzheimer's disease, Parkinson'sdisease and Huntington's disease; cognitive dysfunctions, preferablycognitive deficiency states, particularly preferably memory disorders;inflammations, preferably inflammations of the intestine, the eyes, thebladder, the skin or the nasal mucous membrane; urinary incontinence;overactive bladder (OAB); medication dependency; misuse of medication;withdrawal symptoms in medication dependency; development of toleranceto medication, preferably development of tolerance to natural orsynthetic opioids; drug dependency; misuse of drugs; withdrawal symptomsin drug dependency; alcohol dependency; misuse of alcohol and withdrawalsymptoms in alcohol dependency.

Particular preference is given to at least one compound according to theinvention and also if appropriate to one or more pharmaceuticallycompatible auxiliaries for use in the treatment and/or prophylaxis ofpain, preferably selected from the group consisting of acute pain,chronic pain, neuropathic pain and visceral pain, and/or urinaryincontinence.

Pharmacological Methods I. Functional Testing Carried Out on theVanilloid Receptor 1 (VRI/TRPV1 Receptor)

The agonistic or antagonistic effect of the substances to be tested onthe rat-species vanilloid receptor 1 (VR1/TRPV1) can be determined usingthe following assay. In this assay, the influx of Ca²⁺ through thereceptor channel is quantified with the aid of a Ca²⁺-sensitive dye(type Fluo-4, Molecular Probes Europe BV, Leiden, the Netherlands) in afluorescent imaging plate reader (FLIPR, Molecular Devices, Sunnyvale,USA).

Method:

Complete medium: 50 ml HAMS F12 nutrient mixture (Gibco Invitrogen GmbH,Karlsruhe, Germany) with

10% by volume of FCS (foetal calf serum, Gibco Invitrogen GmbH,Karlsruhe, Germany, heat-inactivated);

2 mM L-glutamine (Sigma, Munich, Germany);

1% by weight of AA solution (antibiotic/antimyotic solution, PAA,Pasching, Austria) and 25 ng/ml NGF medium (2.5 S, Gibco InvitrogenGmbH, Karlsruhe, Germany)

Cell culture plate: Poly-D-lysine-coated, black 96-well plates having aclear base (96-well black/clear plate, BD Biosciences, Heidelberg,Germany) are additionally coated with laminin (Gibco Invitrogen GmbH,Karlsruhe, Germany), the laminin being diluted with PBS (Ca—Mg-free PBS,Gibco Invitrogen GmbH, Karlsruhe, Germany) to a concentration of 100μg/ml. Aliquots having a laminin concentration of 100 μg/ml are removedand stored at −20° C. The aliquots are diluted with PBS in a ratio of1:10 to 10 μg/ml of laminin and respectively 50 μL of the solution arepipetted into a recess in the cell culture plate. The cell cultureplates are incubated for at least two hours at 37° C., the excesssolution is removed by suction and the recesses are each washed twicewith PBS. The coated cell culture plates are stored with excess PBSwhich is not removed until just before the feeding of the cells.

Preparation of the Cells:

The vertebral column is removed from decapitated rats and placedimmediately into cold HBSS buffer (Hank's buffered saline solution,Gibco Invitrogen GmbH, Karlsruhe, Germany), i.e. buffer located in anice bath, mixed with 1% by volume (percent by volume) of an AA solution(antibiotic/antimyotic solution, PAA, Pasching, Austria). The vertebralcolumn is cut longitudinally and removed together with fasciae from thevertebral canal. Subsequently, the dorsal root ganglia (DRG) are removedand again stored in cold HBSS buffer mixed with 1% by volume of an AAsolution. The DRG, from which all blood remnants and spinal nerves havebeen removed, are transferred in each case to 500 μL of cold type 2collagenase (PAA, Pasching, Austria) and incubated for 35 minutes at 37°C. After the addition of 2.5% by volume of trypsin (PAA, Pasching,Austria), incubation is continued for 10 minutes at 37° C. Aftercomplete incubation, the enzyme solution is carefully pipetted off and500 μL of complete medium are added to each of the remaining DRG. TheDRG are respectively suspended several times, drawn through cannulae No.1, No. 12 and No. 16 using a syringe and transferred to a 50 ml Falcontube which is filled up to 15 ml with complete medium. The contents ofeach Falcon tube are respectively filtered through a 70 μm Falcon filterelement and centrifuged for 10 minutes at 1,200 rpm and RT. Theresulting pellet is respectively taken up in 250 μL of complete mediumand the cell count is determined.

The number of cells in the suspension is set to 3×10⁵ per ml and 150 μLof this suspension are in each case introduced into a recess in the cellculture plates coated as described hereinbefore. In the incubator theplates are left for two to three days at 37° C., 5% by volume of CO₂ and95% relative humidity. Subsequently, the cells are loaded with 2 μM ofFluo-4 and 0.01% by volume of Pluronic F127 (Molecular Probes Europe BV,Leiden, the Netherlands) in HBSS buffer (Hank's buffered salinesolution, Gibco Invitrogen GmbH, Karlsruhe, Germany) for 30 min at 37°C., washed 3 times with HBSS buffer and after further incubation for 15minutes at RT used for Ca²⁺ measurement in a FLIPR assay. TheCa²⁺-dependent fluorescence is in this case measured before and afterthe addition of substances (λex=488 nm, λem=540 nm). Quantification iscarried out by measuring the highest fluorescence intensity (FC,fluorescence counts) over time.

FLIPR Assay:

The FLIPR protocol consists of 2 substance additions. First thecompounds to be tested (10 μM) are pipetted onto the cells and the Ca²⁺influx is compared with the control (capsaicin 10 μM). This provides theresult in % activation based on the Ca²⁺ signal after the addition of 10μM of capsaicin (CP). After 5 minutes' incubation, 100 nM of capsaicinare applied and the Ca²⁺ influx is also determined.

Desensitising agonists and antagonists lead to suppression of the Ca²⁺influx. The % inhibition is calculated compared to the maximumachievable inhibition with 10 μM of capsaicin.

Triple analyses (n=3) are carried out and repeated in at least 3independent experiments (N=4).

Starting from the percentage displacement caused by differentconcentrations of the compounds to be tested of general formula I, IC₅₀inhibitory concentrations which cause a 50-percent displacement ofcapsaicin were calculated. K_(i) values for the test substances wereobtained by conversion by means of the Cheng-Prusoff equation (Cheng,Prusoff; Biochem. Pharmacol. 22, 3099-3108, 1973).

II. Functional Tests Carried Out on the Vanilloid Receptor (VR1)

The agonistic or antagonistic effect of the substances to be tested onthe vanilloid receptor 1 (VR1) can also be determined using thefollowing assay. In this assay, the influx of Ca²⁺ through the channelis quantified with the aid of a Ca²⁺-sensitive dye (type Fluo-4,Molecular Probes Europe BV, Leiden, the Netherlands) in a fluorescentimaging plate reader (FLIPR, Molecular Devices, Sunnyvale, USA).

Method:

Chinese hamster ovary cells (CHO K1 cells, European Collection of CellCultures (ECACC) United Kingdom) are stably transfected with the VR1gene. For functional testing, these cells are plated out onpoly-D-lysine-coated black 96-well plates having a clear base (BDBiosciences, Heidelberg, Germany) at a density of 25,000 cells/well. Thecells are incubated overnight at 37° C. and 5% CO₂ in a culture medium(Ham's F12 nutrient mixture, 10% by volume of FCS (foetal calf serum),18 μg/ml of L-proline). The next day the cells are incubated with Fluo-4(Fluo-4 2 μM, 0.01% by volume of Pluronic F127, Molecular Probes in HBSS(Hank's buffered saline solution), Gibco Invitrogen GmbH, Karlsruhe,Germany) for 30 minutes at 37° C. Subsequently, the plates are washedthree times with HBSS buffer and after further incubation for 15 minutesat RT used for Ca²⁺ measurement in a FLIPR assay. The Ca²⁺-dependentfluorescence is measured before and after the addition of the substancesto be tested (λex wavelength=488 nm, λem=540 nm). Quantification iscarried out by measuring the highest fluorescence intensity (FC,fluorescence counts) over time.

FLIPR Assay:

The FLIPR protocol consists of 2 substance additions. First thecompounds to be tested (10 μM) are pipetted onto the cells and the Ca²⁺influx is compared with the control (capsaicin 10 μM) (% activationbased on the Ca²⁺ signal after the addition of 10 μM of capsaicin).After 5 minutes' incubation, 100 nM of capsaicin are applied and theCa²⁺ influx is also determined.

Desensitising agonists and antagonists led to suppression of the Ca²⁺influx. The % inhibition is calculated compared to the maximumachievable inhibition with 10 μM of capsaicin.

Starting from the percentage displacement caused by differentconcentrations of the compounds to be tested of general formula I, IC₅₀inhibitory concentrations which cause a 50-percent displacement ofcapsaicin were calculated. K_(i) values for the test substances wereobtained by conversion by means of the Cheng-Prusoff equation (Cheng,Prusoff; Biochem. Pharmacol. 22, 3099-3108, 1973).

III. Formalin Test Carried Out on Mice

In the formalin test, the testing to determine the antinociceptiveeffect of the compounds according to the invention is carried out onmale mice (NMRI, 20 to 30 g body weight, Iffa, Credo, Belgium).

In the formalin test as described by D. Dubuisson et al., Pain 1977, 4,161-174, a distinction is drawn between the first (early) phase (0 to 15minutes after the injection of formalin) and the second (late) phase (15to 60 minutes after the injection of formalin). The early phase, as animmediate reaction to the injection of formalin, is a model of acutepain, whereas the late phase is regarded as a model of persistent(chronic) pain (T. J. Coderre et al., Pain 1993, 52, 259-285). Thecorresponding descriptions in the literature are introduced herewith byway of reference and form part of the disclosure.

The compounds according to the invention are tested in the second phaseof the formalin test to obtain information about the effects ofsubstances on chronic/inflammatory pain.

The moment at which the compounds according to the invention are appliedbefore the injection of formalin is selected as a function of the typeof application of the compounds according to the invention. 10 mg of thetest substances/kg of body weight are applied intravenously 5 minutesbefore the injection of formalin which is carried out by a singlesubcutaneous injection of formalin (20 μL, 1% aqueous solution) into thedorsal side of the right hind paw, thus inducing in free moving testanimals a nociceptive reaction which manifests itself in marked lickingand biting of the paw in question.

Subsequently, the nociceptive behaviour is continuously detected byobserving the animals over a test period of three minutes in the second(late) phase of the formalin test (21 to 24 minutes after the injectionof formalin). The pain behaviour is quantified by adding up the secondsover which the animals display licking and biting of the paw in questionduring the test period.

The comparison is carried out respectively with control animals whichare given vehicles (0.9% aqueous sodium chloride solution) instead ofthe compounds according to the invention before the administration offormalin. Based on the quantification of the pain behaviour, the effectof the substance is determined in the formalin test as a percentagechange relative to the corresponding control.

After the injection of substances having an antinociceptive effect inthe formalin test, the described behaviour of the animals, i.e. lickingand biting, is reduced or eliminated.

IV. Testing of Analgesic Efficacy in the Writhing Test

The testing of analgesic efficacy in the compounds according to theinvention of general formula I was carried out by phenylquinone-inducedwrithing in mice (modified in accordance with I. C. Hendershot and J.Forsaith (1959), J. Pharmacol. Exp. Ther. 125, 237-240). Thecorresponding description in the literature is introduced herewith byway of reference and forms part of the disclosure.

Male NMRI mice weighing from 25 to 30 g were used for this purpose. 10minutes after intravenous administration of the compounds to be tested,groups of 10 animals per compound dose received 0.3 ml/mouse of a 0.02%aqueous solution of phenylquinone (phenylbenzoquinone, Sigma,Deisenhofen, Germany; solution prepared by adding 5% by weight ofethanol and storage in a water bath at 45° C.) appliedintraperitoneally. The animals were placed individually into observationcages. A pushbutton counter was used to record the number ofpain-induced stretching movements (what are known as writhingreactions=straightening of the torso with stretching of the rearextremities) for 5 to 20 minutes after the administration ofphenylquinone. The control was provided by animals which had receivedonly physiological saline solution. All the compounds were tested at thestandard dosage of 10 mg/kg.

V. Hypothermia Assay Carried Out on Mice Description of the Method:

The hypothermia assay is carried out on male NMRI mice (weight 25-35grams, breeder IFFA CREDO, Brussels, Belgium). The animals were keptunder standardised conditions: light/dark rhythm (from 6:00 to 18:00light phase; from 18:00 to 6:00 dark phase), RT 19-22° C., relativehumidity 35-70%, 15 room air changes per hour, air movement <0.2 m/sec.The animals received standard feed (ssniff R/M-Haltung, ssniffSpezialdiäten GmbH, Soest, Germany) and tap water. Water and feed werewithdrawn during the experiment. All the animals were used only onceduring the experiment. The animals had an acclimatisation period of atleast 5 days.

Acute application of capsaicin (VR-1 agonist) leads to a drop in thecore temperature of the body in rats and mice due to stimulation of heatsensors. Only specifically effective VR-1 receptor antagonists canantagonise the capsaicin-induced hypothermia. By contrast, hypothermiainduced by morphine is not antagonised by VR-1 antagonists. This modelis therefore suitable for identifying substances with VR-1 antagonisticproperties via their effect on body temperature.

Measurement of the core temperature was carried out using a digitalthermometer (Thermalert TH-5, physitemp, Clifton N.J., USA). The sensingelement is in this case inserted into the rectum of the animals.

To give an individual basic value for each animal, the body temperatureis measured twice at an interval of approx. half an hour. One group ofanimals (n=6 to 10) then receives an intraperitoneal (i.p.) applicationof capsaicin 3 mg/kg and vehicle (control group). Another group ofanimals receives the substance to be tested (i.v. or p.o.) andadditionally capsaicin (3 mg/kg) i.p. The test substance is applied i.v.10 min, or p.o 15 minutes, prior to capsaicin. The body temperature isthen measured 7.5/15 and 30 min following capsaicin (i.v.+i.p.) or15/30/60/90/120 min (p.o.+i.p.) following capsaicin. In addition, onegroup of animals is treated with the test substance only and one groupwith vehicle only. The evaluation or representation of the measuredvalues as the mean+/−SEM of the absolute values is carried out as agraphical representation. The antagonistic effect is calculated as thepercentage reduction of the capsaicin-induced hypothermia.

VI. Neuropathic Pain in Mice

Efficacy in neurotic pain was tested using the Bennett model (chronicconstriction injury; Bennett und Xie, 1988, Pain 33: 87-107).

Three loose ligatures are tied around the right ischiadic nerve ofKetavet/Rompun-anaesthetised NMRI mice weighing 16-18 g. The animalsdevelop hypersensitivity of the innervated paw caused by the damagednerve, which hypersensitivity is quantified, following a recovery phaseof one week, over a period of approximately three weeks by means of acold metal plate (temperature 4° C.) (cold allodynia). The animals areobserved on this plate over a period of 2 min and the withdrawalreactions of the damaged paw are counted. Based on the pre-value priorto the application of the substance, the substance's effect over acertain period of time is determined at various points in time (forexample 15, 30, 45, or 60 min following application) and the resultantarea under the curve (AUC) and/or the inhibition of cold allodynia atthe individual measuring points is/are expressed as a percentage effectrelative to the vehicle control (AUC) or to the starting value(individual measuring points). The group size is n=10, the significanceof an antiallodynic effect (*=p<0.05) is determined with the aid of ananalysis of variance with repeated measures and Bonferroni post hocanalysis.

The invention will be described hereinafter with the aid of a fewexamples. This description is intended merely by way of example and doesnot limit the general idea of the invention.

EXAMPLES

The indication “equivalents” (“eq.”) means molar equivalents, “RT” meansroom temperature, “M” and “N” are indications of concentration in mol/l,“aq.” means aqueous, “sat.” means saturated, “sol.” means solution,“conc.” means concentrated.

Further Abbreviations:

AcOH acetic acidd daysBOP 1-benzotriazolyloxy-tris-(dimethylamino)phosphoniumhexafluorophosphatebrine saturated sodium chloride solution (NaCl sol.)bipy 2,2′-bipyridine/2,2′-bipyridylBoc tert-butyloxycarbonylDCC N,N′-dicyclohexylcarbodiimideDCM dichloromethane

DIPEA N,N-diisopropylethylamine DMF N,N-dimethylformamide

DMAP 4-dimethylaminopyridineEDC N-(3-dimethylaminopropyl)-N′-ethylcarbodiimideEDCI N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochlorideEE ethyl acetateether diethyl etherEtOH ethanolsat. saturatedh hour(s)H₂O water

HOBt N-hydroxybenzotriazole

LAH lithium aluminium hydrideLG leaving groupm/z mass-to-charge ratioMeOH methanolmin minutesMS mass spectrometryNA not availableNEt₃ triethylamineR_(f) retention factorSC silica gel column chromatographyTHF tetrahydrofuranTFA trifluoroacetic acidTLC thin layer chromatographyvv volume ratio

The yields of the compounds prepared were not optimised.

All temperatures are uncorrected.

All starting materials which are not explicitly described were eithercommercially available (the details of suppliers such as for exampleAcros, Avocado, Aldrich, Bachem, Fluka, Lancaster, Maybridge, Merck,Sigma, TCI, Oakwood, etc. can be found in the Symyx® Available ChemicalsDatabase of MDL, San Ramon, US, for example) or the synthesis thereofhas already been described precisely in the specialist literature(experimental guidelines can be looked up in the Reaxys® Database ofElsevier, Amsterdam, NL, for example) or can be prepared using theconventional methods known to the person skilled in the art.

The stationary phase used for the column chromatography was silica gel60 (0.0.0-0.063 mm) from E. Merck, Darmstadt. The thin-layerchromatographic tests were carried out using HPTLC precoated plates,silica gel 60 F 254, from E. Merck, Darmstadt.

The mixing ratios of solvents, mobile solvents or for chromatographictests are respectively specified in volume/volume.

All the intermediate products and exemplary compounds were analyticallycharacterised by means of ¹H-NMR spectroscopy. In addition, massspectrometry tests (MS, m/z indication for [M+H]⁺) were carried out forall the exemplary compounds and selected intermediate products.

In step j01 an acid halide J-0, in which Hal preferably represents Cl orBr, can be esterified using methanol to form the compound J-I by meansof methods with which the person skilled in the art is familiar.

In step j02 the methyl pivalate J-I can be converted into anoxoalkylnitrile J-II, wherein X═CR³, by means of methods known to theperson skilled in the art, such as for example using an alkyl nitrileR³CH₂—CN, if appropriate in the presence of a base.

In step j03 the compound J-II can be converted into an amino-substitutedpyrazolyl derivative J-III, wherein X═CR³, by means of methods known tothe person skilled in the art, such as for example using hydrazinehydrate, with cyclisation.

In step j04 the amino compound J-III can first be converted into adiazonium salt by means of methods known to the person skilled in theart, such as for example using nitrite, and the diazonium salt can beconverted into a cyano-substituted pyrazolyl derivative J-IV, whereinX═CR³, with elimination of nitrogen using a cyanide, if appropriate inthe presence of a coupling reagent.

In step j05 the compound J-IV can be substituted in the N position bymeans of methods known to the person skilled in the art, for exampleusing a halide R¹—Hal, if appropriate in the presence of a base and/or acoupling reagent, wherein Hal is preferably Cl, Br or I, or using aboronic acid B(OH)₂R¹ or a corresponding boronic acid ester, ifappropriate in the presence of a coupling reagent and/or a base and thecompound J-V, wherein X═CR³, can in this way be obtained. If R¹ islinked to general formula (I) via a heteroatom (if R¹ representssubstructure (T-1), for example, in which o represents 1 and Y canrepresent inter alia O, S, S(═O)₂, NH—C(═O) or NR¹²), then thesubstitution can be carried out using methods known to the personskilled in the art, for example with the aid ofhydroxylamine-O-sulphonic acid and subsequent conversion into secondaryor tertiary amines, wherein Y═NR¹³. In the case of Y═O, the substitutioncan be carried out using methods known to the person skilled in the art,for example with the aid of peroxy reagents and subsequent conversioninto ether. In the case of Y═S(═O)₂, the substitution can be carried outby sulphonylation with sulphonyl chlorides, for example. In the case ofY═S, the preparation can for example be carried out by reaction withdisulphides or else with sulphenyl chlorides or sulphene amides, or elseby transformation into the mercaptan by means of methods known to theperson skilled in the art and subsequent conversion into the thioether.

Alternatively, a second synthesis pathway, in which in step k01 an esterK-0 is first reduced to form the aldehyde K−1 by means of methods knownto the person skilled in the art, for example using suitablehydrogenation reagents such as metal hydrides, is suitable for preparingthe compound J-V, wherein X═CR³.

In step k02 the aldehyde K−1 can then be reacted with a hydrazine K-V,which can be obtained in step k05, starting from the primary amine K-IV,by means of methods known to the person skilled in the art, to form thehydrazine K-II by means of methods known to the person skilled in theart with elimination of water.

In step k03 the hydrazine K-II can be halogenated, preferablychlorinated, by means of methods known to the person skilled in the artwith the double bond intact, such as for example using a chlorinationreagent such as NCS, and the compound K-III can in this way be obtained.

In step k04 the hydrazonoyl halide K-III can be converted into acyano-substituted compound J-V, wherein X═CR³, by means of methods knownto the person skilled in the art, such as for example using ahalogen-substituted nitrile, with cyclisation.

In step j06 the compound J-V can be hydrogenated by means of methodsknown to the person skilled in the art, for example using a suitablecatalyst such as palladium/activated carbon or using suitablehydrogenation reagents, and the compound (II) can in this way beobtained.

In step j07 the compound (II) can be converted into the compound (V) bymeans of methods known to the person skilled in the art, such as forexample using phenyl chloroformate, if appropriate in the presence of acoupling reagent and/or a base. In addition to the methods disclosed inthe present document for preparing unsymmetrical ureas using phenylchloroformate, there are further processes with which the person skilledin the art is familiar, based on the use of activated carbonic acidderivatives or isocyanates, if appropriate.

In step j08 the amine (VI) can be converted into the urea compound (I)(wherein A=N). This can be achieved by reaction with (V) by means ofmethods with which the person skilled in the art is familiar, ifappropriate in the presence of a base.

In step j09 the amine (II) can be converted into the amide (I) (whereinA=C—R^(5b)). This can for example be achieved by reaction with an acidhalide, preferably a chloride of formula (IV) by means of methods withwhich the person skilled in the art is familiar, if appropriate in thepresence of a base or by reaction with an acid of formula (III), ifappropriate in the presence of a suitable coupling reagent, for exampleHATU or CDI, if appropriate with the addition of a base. Further, theamine (II) may be converted into the amide (I) (wherein A=C—R^(5b)) byreaction of a compound (IVa) by means of methods with which the personskilled in the art is familiar, if appropriate in the presence of abase.

For preparing compounds (1I), wherein X═N, it is necessary to take athird synthesis route according to the general reaction scheme 1b. Thecompounds (1I) which are then obtained, wherein X═N, can subsequently befurther reacted in accordance with the above-described steps j07-j09.

In step I01 a carboxylic acid alkyl ester L-0, preferably a methyl orethyl ester, can be reacted with hydrazine hydrate to form the hydrazideL-1 by means of methods with which the person skilled in the art isfamiliar.

In step I02 the amino-substituted nitrile L-2 or the salts thereof canbe reacted with boc anhydride to form the urethane L-3 by means ofmethods with which the person skilled in the art is familiar.

In step I03 L-1 and L-3 can be condensed in the presence of a base,preferably an alkali alcoholate, particularly preferably sodiummethanolate, to form the triazole L-4, wherein X═N, by means of methodswith which the person skilled in the art is familiar.

In step I04 the compound L-4, wherein X═N, can be substituted in the Nposition by means of methods known to the person skilled in the art, ina manner similar to the step j05 according to general reaction scheme 1aby means of the methods described hereinbefore, and compound L-5,wherein X═N, can in this way be obtained.

In step I05 the ester group in L-4 can be eliminated in the presence ofan acid, preferably trifluoroacetic acid or hydrochloric acid, by meansof methods known to the person skilled in the art, and the amine (II)can in this way be obtained.

The compounds according to general formula (I), wherein A=N, may befurther prepared by a reaction sequence according to general reactionscheme 1c.

In step v1 the compound (VI) can be converted into the compound (VIa) bymeans of methods known to the person skilled in the art, such as forexample using phenyl chloroformate, if appropriate in the presence of acoupling reagent and/or a base. In addition to the methods disclosed inthe present document for preparing unsymmetrical ureas using phenylchloroformate, there are further processes with which the person skilledin the art is familiar, based on the use of activated carbonic acidderivatives or isocyanates, if appropriate.

In step v2 the amine (II) can be converted into the urea compound (I)(wherein A=N). This can be achieved by reaction with (VIa) by means ofmethods with which the person skilled in the art is familiar, ifappropriate in the presence of a base.

The methods with which the person skilled in the art is familiar forcarrying out the reaction steps j01 to j09 and also k01 to k05 and l01to l05 as well as v1 and v2 may be inferred from the standard works onorganic chemistry such as, for example, J. March, Advanced OrganicChemistry, Wiley & Sons, 6th edition, 2007; F. A. Carey, R. J. Sundberg,Advanced Organic Chemistry, Parts A and B, Springer, 5th edition, 2007;team of authors, Compendium of Organic Synthetic Methods, Wiley & Sons.In addition, further methods and also literature references can beissued by the common databases such as, for example, the Reaxys®database of Elsevier, Amsterdam, NL or the SciFinder® database of theAmerican Chemical Society, Washington, US.

Synthesis of Intermediate Products 1. Synthesis of3-tert-butyl-1-methyl-1H-pyrazol-5-yl-methanamine (steps j01-j06)

Step j01: Pivaloyl chloride (J-0) (1 eq., 60 g) was added dropwise to asolution of MeOH (120 ml) within 30 min at 0° C. and the mixture wasstirred for 1 h at room temperature. After the addition of water (120ml), the separated organic phase was washed with water (120 ml), driedover sodium sulphate and codistilled with dichloromethane (150 ml). Theliquid product J-I was able to be obtained at 98.6% purity (57 g).

Step j02: NaH (50% in paraffin oil) (1.2 eq., 4.6 g) was dissolved in1,4-dioxane (120 ml) and the mixture was stirred for a few minutes.Acetonitrile (1.2 eq., 4.2 g) was added dropwise within 15 min and themixture was stirred for a further 30 min. The methyl pivalate (J-I) (1eq., 10 g) was added dropwise within 15 min and the reaction mixture wasrefluxed for 3 h. After complete reaction, the reaction mixture wasplaced in iced water (200 g), acidified to pH 4.5 and extracted withdichloromethane (12×250 ml). The combined organic phases were dried oversodium sulphate, distilled and after recrystallisation from hexane (100ml) 5 g of the product (J-II) (51% yield) was able to be obtained as asolid brown substance.

Step j03: At room temperature 4,4-dimethyl-3-oxopentanenitrile (J-II) (1eq., 5 g) was taken up in EtOH (100 ml), mixed with hydrazine hydrate (2eq., 4.42 g) and refluxed for 3 h. The residue obtained after removal ofthe EtOH by distillation was taken up in water (100 ml) and extractedwith EE (300 ml). The combined organic phases were dried over sodiumsulphate, the solvent was removed under vacuum and the product (J-III)(5 g, 89% yield) was obtained as a light red solid afterrecrystallisation from hexane (200 ml).

Step j04: 3-Tert-butyl-1H-pyrazol-5-amine (J-III) (1 eq., 40 g) wasdissolved in dilute HCl (120 ml of HCl in 120 ml of water) and mixeddropwise with NaNO₂ (1.03 eq., 25 g in 100 ml) at 0-5° C. over a periodof 30 min. After stirring for 30 minutes, the reaction mixture wasneutralised with Na₂CO₃. A diazonium salt obtained by reaction of KCN(2.4 eq., 48 g), water (120 ml) and CuCN (1.12 eq., 31 g) was addeddropwise to the reaction mixture within 30 min and the mixture wasstirred for a further 30 min at 75° C. After complete reaction, thereaction mixture was extracted with EE (3×500 ml), the combined organicphases were dried over sodium sulphate and the solvent was removed undervacuum. The purification (SiO₂, 20% EE/hexane) of the residue by columnchromatography produced a white solid (J-IV) (6.5 g, 15.1% yield).

Step j05 (Method 1):

3-tert.-butyl-1H-pyrazol-5-carbonitrile (J-IV) (10 mmol) was added to asuspension of NaH (60%) (12.5 mmol) in DMF (20 ml) at room temperaturewhile stirring. After stirring for 15 minutes, methyl iodide (37.5 mmol)was added dropwise to this reaction mixture at room temperature. Afterstirring for 30 min at 100° C., the reaction mixture was mixed withwater (150 ml) and extracted with dichloromethane (3×75 ml). Thecombined organic extracts were washed with water (100 ml) and sat. NaClsolution (100 ml) and dried over magnesium sulphate. After removal ofthe solvent under vacuum, the residue was purified by columnchromatography (SiO₂, various mixtures of EE and cyclohexane as themobile solvent) and the product J-V was obtained.

Step j06: Method 1:

J-V was dissolved together with palladium on carbon (10%, 500 mg) andconcentrated HCl (3 ml) in MeOH (30 ml) and exposed to a hydrogenatmosphere for 6 hours at room temperature. The reaction mixture wasfiltered over celite and the filtrate was concentrated under vacuum. Theresidue was purified by means of flash chromatography (SiO₂, EE) and theproduct (II) was in this way obtained.

Method 2:

J-V was dissolved in THF (10 ml) and BH₃.S(CH₃)₂ (2.0 M in THF, 3 ml, 3equivalent) was added thereto. The reaction mixture was heated to refluxfor 8 hours, aq. 2 N HCl (2 N) was added thereto and the reactionmixture was refluxed for a further 30 minutes. The reaction mixture wasmixed with aq. NaOH solution (2N) and washed with EE. The combinedorganic phases were washed with sat. aq. NaCl solution and dried overmagnesium sulphate. The solvent is removed under vacuum and the residueis purified by column chromatography (SiO₂, various mixtures ofdichloromethane and methanol as the mobile solvent) and the product (II)(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)methanamine) is in this wayobtained.

2. The Following Further Intermediate Products were Synthesised in aSimilar Manner Using the Process Described Hereinbefore Under 1

3-tert-butyl-1-hexyl-1H-pyrazol-5-yl-methanamine

3. Alternatively, Step j05 can Also be Carried Out as Follows (Method 2)Step j05 (Method 2):

A mixture of 3-tert-butyl-1H-pyrazol-5-carbonitrile (J-IV) (10 mmol), aboronic acid B(OH)₂R¹ or a corresponding boronic acid ester (20 mmol)and copper (II) acetate (15 mmol) is placed in dichloromethane (200 ml),mixed with pyridine (20 mmol) while stirring at room temperature and themixture is stirred for 16 h. After removal of the solvent under vacuum,the residue obtained is purified by column chromatography (SiO₂, variousmixtures of EE and cyclohexane as the mobile solvent) and the productJ-V is in this way obtained.

The following further intermediate products were prepared in this way(steps j01-j06):

(3-tert-butyl-1-cyclohexenyl-1H-pyrazol-5-yl)methanamine(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)methanamine(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)methanamine(3-tert-butyl-1-(4-tert-butylphenyl)-1H-pyrazol-5-yl)methanamine(3-tert-butyl-1-(4-chlorophenyl)-1H-pyrazol-5-yl)methanamine(3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methanamine(3-tert-butyl-1-(3-chloro-4-fluorophenyl)-1H-pyrazol-5-yl)methanamine(3-tert-butyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl)methanamine(E)-(3-tert-butyl-1-(4-methylstyryl)-1H-pyrazol-5-yl)methanamine

4. Synthesis of1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl-methanamine(steps k01-k05 and j06)

Step k01: LAlH (lithium aluminium hydride) (0.25 eq., 0.7 g) wasdissolved in dry diethyl ether (30 ml) under a protective gas atmosphereand stirred for 2 h at room temperature. The suspension obtained wastaken up in diethyl ether (20 ml). Ethyl-2,2,2-trifluoroacetate (K-0) (1eq., 10 g) was taken up in dry diethyl ether (20 ml) and added dropwiseto the suspension at −78° C. over a period of 1 h. The mixture was thenthe stirred for a further 2 h at −78° C. EtOH (95%) (2.5 ml) was thenadded dropwise, the reaction mixture was heated to room temperature andplaced on iced water (30 ml) with concentrated H₂SO₄ (7.5 ml). Theorganic phase was separated and concentrated under vacuum and thereaction product K-I was immediately introduced into the next reactionstep k02.

Step k05: 3-chloroaniline (K-IV) (1 eq., 50 g) was dissolved at −5 to 0°C. in concentrated HCl (300 ml) and stirred for 10 min. A mixture ofNaNO₂ (1.2 eq., 32.4 g), water (30 ml), SnCl₂.2H₂O (2.2 eq., 70.6 g) andconcentrated HCl (100 ml) was added dropwise over a period of 3 h whilemaintaining the temperature. After stirring for a further 2 h at −5 to0° C., the reaction mixture was set to pH 9 using NaOH solution andextracted with EE (250 ml). The combined organic phases were dried overmagnesium sulphate and the solvent was removed under vacuum. Thepurification by column chromatography (SiO₂, 8% EE/hexane) produced 40 g(72% yield) of (3-chlorophenyl)hydrazine (K-IV) as a brown oil.

Step k02: The aldehyde (K-I) (2 eq., 300 ml) obtained from k01 and(3-chlorophenyl)hydrazine (K-IV) (1 eq., 20 g) were placed in EtOH (200ml) and refluxed for 5 h. The solvent was removed under vacuum, theresidue was purified by column chromatography (SiO₂, hexane) and theproduct (25 g, 72% yield) K-II was obtained as a brown oil.

Step k03: The hydrazine K-II (1 eq., 25 g) was dissolved in DMF (125ml). N-chlorosuccinimide (1.3 eq., 19.5 g) was added portionwise at roomtemperature within 15 min and the mixture was stirred for 3 h. The DMFwas removed by distillation and the residue was taken up in EE. The EEwas removed under vacuum, the residue obtained was purified by columnchromatography (SiO₂, hexane) and the product K-III (26.5 g, 92% yield)was obtained as a pink-coloured oil.

Step k04: At room temperature the hydrazonoyl chloride K-III (1 eq., 10g) was taken up in toluene (150 ml) and mixed with 2-chloroacrylonitrile(2 eq., 6.1 ml) and TEA (2 eq., 10.7 ml). This reaction mixture wasstirred for 20 h at 80° C. The mixture was then diluted with water (200ml) and the phases were separated. The organic phase was dried overmagnesium sulphate and the solvent was removed under vacuum. The residuewas purified by means of column chromatography (SiO₂, 5% EE/hexane) andthe product (5.5 g, 52% yield) was obtained as a white solid J-V.

Step j06 (Method 3):

The carbonitrile J-V (1 eq., 1 g) was dissolved in methanolic ammoniasolution (150 ml, 1:1) and hydrogenated in an H-cube (10 bar, 80° C., 1ml/min, 0.25 mol/L). After removal of the solvent under vacuum,(1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine (II)was able to be obtained as a white solid (0.92 g, 91% yield).

5. The Following Further Intermediate Products were Synthesised in aSimilar Manner Using the Process Described Hereinbefore Under 4

(1-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine(1-(3-chloro-4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine

6. Preparation of Selected Acids of General Formula (III) 6.1 Synthesisof 2-(4-(N,N-dimethylsulphamoyl)-3-fluorophenyl)propanoic acid

Step a: 4-bromo-2-fluorobenzene sulphonyl chloride (9.15 mmol, 2.5 g)was dissolved in dichloromethane (75 ml) at room temperature, mixed withdimethylamine (2 mol/l in MeOH) (18.3 mmol, 9.15 ml) and stirred for 2 hat room temperature after addition of the pyridine (32 mmol, 2.58 ml).The reaction mixture was mixed with water (75 ml) and the organic phasewas separated off. The aqueous phase was extracted with EE (2×75 ml),the organic phases were combined and dried over magnesium sulphate.After removal of the solvent under vacuum, 2.51 g (97% yield) of theproduct could be obtained.

Step b: step-a-product (8.9 mmol, 2.5 g) and ethyl-2-chloropropionate(11.5 mmol, 1.57 g) were dissolved in DMF (15 ml) at room temperatureunder a protective gas atmosphere. Subsequently, manganese (17.7 mmol,0.974 g), (2,2′-bipyridine) nickel (II) dibromide (0.62 mmol, 0.231 g)and TFA (0.23 mmol, 18 μL) were added and stirred for 48 h at 50° C.After cooling of the reaction mixture to room temperature, the mixturewas hydrolysed with 1 N HCl (25 ml) and the mix was extracted withdiethyl ether (3×25 ml). The combined organic phases were washed withwater (25 ml) and aq. sat. NaCl solution (25 ml) and dried overmagnesium sulphate. The solvent was removed under vacuum and the residuewas purified by means of column chromatography (SiO₂,dichloromethane/MeOH=15:1) and the product was in this way obtained.

Step c: Step-b-product (5.9 mmol, 1.8 g) was dissolved in a THF-watermix (15 ml, 2:1), LiOH (17.8 mmol, 0.414 g) was added and refluxed for10 h. The reaction mixture was extracted with diethyl ether (25 ml), theaqueous phase was acidified to pH 2 using 1 N HCl and extracted with EE(3×25 ml). The combined organic phases were dried over magnesiumsulphate and the solvent was concentrated to dryness under vacuum.2-(4-(N,N-dimethylsulphamoyl)-3-fluorophenyl)propanoic acid (C) could beobtained at a 48% yield (0.78 g).

6.2 Synthesis of 2-(4-methoxy-3,5-dimethylphenyl)acetic acid

Step a: Bromo-2,6-dimethylanisol (23.2 mmol, 5 g), CuBr (46.5 mmol, 6.67g) and diethyl malonate (46.5 mmol, 7.09 ml) were dissolved in1,4-dioxane (30 ml). NaH (60% in mineral oil) (51.1 mmol, 1.225 g) wasadded slowly at room temperature while stirring and the mixture wasstirred for 10 h at 100° C. After cooling of the reaction mixture, abrown solid was removed by filtration and the filtrate was concentratedunder vacuum. The purification by column chromatography (SiO₂,EE/cyclohexane, 1: 2) produces 0.87 g (13% yield) of the malonic aciddiethyl ester.

Step b: The malonic acid diethyl ester (0.34 mmol, 0.1 g) obtained wasthen dissolved in 2 N NaOH/THF:H₂O (1:1) (350 μL) and refluxed for 3 h.After acidifying the reaction mixture to pH 1 using conc. HCl, themixture was stirred for a further hour at room temperature. The solutionwas then set to pH 13 using 1 N NaOH and extracted with diethyl ether(20 ml). The aqueous phase was set to pH 5 using 1 N HCl and extractedwith EE (3×20 ml). The combined organic phases were washed with sat.NaCl solution, dried over magnesium sulphate and filtered. After removalof the solvent under vacuum, 0.021 g (32% yield) of the desired2-(4-methoxy-3,5-dimethylphenyl)acetic acid could be obtained.

6.3 Synthesis of 2-(3,5-difluoro-4-hydroxyphenyl)acetic acid (employedfor the synthesis of example compound no. 147)

Step a: 4-bromo-2,6-difluorophenol (5 g, 23.92 mmol) was dissolved indimethylformamide (50 mL) in 250 ml round bottom flask equipped withargon atmosphere. Potassium carbonate (5 g, 35.55 mmol) was added andstirred for 10 minutes, followed by addition of benzyl bromide (4.5 g,26.31 mmol) and stirred at ambient temperature for 4 h. TLC showed(hexane, R_(f): 0.8) complete conversion of starting material. Thereaction mixture was diluted with water (500 mL) and extracted withethyl acetate (3×100 mL). The combined organic part was dried overanhydrous magnesium sulfate and concentrated under reduced pressure toafford crude material, which was purified by column chromatography(silica gel: 100-200 mesh, eluent: 5% ethyl acetate in hexane) to affordthe pure compound (7 g, 95.8%).

Step b: In a 50 mL two necked round bottom flask step-a product (2 g,6.68 mmol), ethyl chloroacetate (1.06 g, 8.69 mmol), anddimethylformamide (14 mL) were charged. The system was degassed andrefilled with argon followed by addition of Mn (735 mg, 13.36 mmol) andNiBr₂.bipy (202 mg, 0.53 mmol). Finally trifluoroacetic acid (14 μL) wasadded and the reaction mixture was degassed and refilled with argon.Then it was heated to 65° C. for one and half hour. TLC showed (10%ethyl acetate in hexane, R_(f): 0.4) complete conversion of startingmaterial. The reaction mixture was diluted with water (50 mL) and HCl(4N, 0.5 mL) and extracted with ethyl acetate (3×50 mL). The combinedorganic part was dried over anhydrous magnesium sulfate and concentratedunder reduced pressure to afford crude material which was purified bycolumn chromatography (silica gel: 100-200 mesh, eluent: 10% ethylacetate in hexane) to afford 700 mg product. ¹H NMR (DMSO-d₆, 400 MHz):δ 7.54 (t, 1H), 7.15 (d, 2H), 4.16 (q, 2H), 3.64 (s, 2H), 1.26 (t, 3H).

Step c: Step-b product (700 mg, 2.6 mmol) was dissolved in THF (4 mL).LiOH (4 mL, 1M, 4 mmol) was added to it. The reaction mixture wasstirred at ambient temperature for 2 h. TLC showed (60% ethyl acetate inhexane, R_(f): 0.2) complete conversion of starting material. Thereaction mixture was diluted with water (30 mL) and washed with ethylacetate (2×30 mL). The aqueous part was acidified with 4N HCl (pH˜2) andextracted with in ethyl acetate (3×40 mL). The combined organic layerwas washed with water (50 mL) and brine (50 mL). It was dried overanhydrous magnesium sulfate and concentrated under reduced pressure toafford 500 mg pure compound. ¹H NMR (DMSO-d₆, 400 MHz): δ 12.45 (s, 1H),7.32-7.42 (m, 5H), 7.03 (d, 2H), 5.13 (s, 2H), 3.56 (s, 2H)

Step d: Step-c product (1.4 g, 5 mmol) was dissolved in EtOH (14 mL).Palladium on carbon (140 mg, 10% Pd) was added to it under argonatmosphere. The reaction mixture was hydrogenated at 50 psi hydrogenpressure for 16 h. TLC showed (in ethyl acetate, R_(f): 0.1) completeconversion of starting material. The reaction mixture was filtered overcelite bed and washed with ethyl acetate and concentrated under reducedpressure to afford desired product (800 mg, 84.5%). ¹H NMR (DMSO-d₆, 400MHz): δ 12.38 (bs, 1H), 10.03 (bs, 1H), 6.92 (d, 2H), 3.49 (s, 2H); LCMS[M−H]: 187.

6.4 Synthesis of 2-(3,5-difluoro-4-hydroxyphenyl)propanoic acid(employed for the synthesis of example compound no. 46)

Step a: To a stirred solution of 4-bromo-2,6-difluorophenol (8 g, 38.27mmol) in dimethyl formamide (80 mL), potassium carbonate (7.9 g, 57.41mmol) was added and stirred for 15 minutes at ambient temperature. Thenbenzyl bromide (7.85 g, 45.93 mmol) was added dropwise for 10 minutes.It was allowed to stir at ambient temperature for 10 h. Water (800 mL)was added to it and extracted with ethyl acetate (3×100 mL). Thecombined organic layer was dried over magnesium sulfate and concentratedto afford crude, which was purified through column chromatography(silica gel: 100-200 mesh; eluent: 5% ethyl acetate in hexane) to affordcompound (10.2 g, 87.8%).

Step b: To a stirred solution of step-a product (5 g, 16.72 mmol) intoluene (120 mL), bis(pinacolato)diboron (5 g, 19.68 mmol) was added anddeoxygenated twice. Potassium phenoxide (3.3 g, 24.61 mmol),PdCl₂(PPh₃)₂ (0.35 g, 0.49 mmol) and PPh₃ (0.26 g, 0.98 mmol) were addedsimultaneously to it and again deoxygenated with argon. The reaction washeated at 60° C. and maintained the same temperature for 12 h. Thereaction mixture was filtered through celite bed and the filtrate wastaken in ethyl acetate (200 mL) and was washed with water (2×100 mL).The final organic layer was dried over anhydrous magnesium sulfate andconcentrated to afford the crude compound, which was purified throughcolumn chromatography (silica: 100-200 mesh, eluent: 3% ethyl acetate inhexane) to afford compound (3.0 g, 51.9%). ¹H NMR (DMSO-d₆, 400 MHz):δ7.35-7.42 (m, 6H), 7.24 (d, 2H), 5.2 (s, 2H), 1.27 (s, 12H).

Step c: To a stirred solution of step-b product (2.5 g, 7.22 mmol) in amixture of toluene and EtOH (1:1, 20 mL) compound 4 (2.53 g, 10.83 mmol)was added and deoxygenated twice. PdCl₂ (dppf) (264 mg, 0.36 mmol) and2M sodium carbonate solution (7.2 mL) was added simultaneously andfinally heated at 90° C. for 3 h. The reaction mixture was diluted withwater (100 mL) and was extracted with ethyl acetate (2×50 mL). Thecombined organic layer was dried over anhydrous magnesium sulfate andconcentrated to afford crude compound, which was purified through columnchromatography (silica: 100-200 mesh, eluent: 2% ethyl acetate inhexane) to obtain pure compound (1.2 g, 54.5%). ¹H NMR (DMSO-d₆, 400MHz): δ 7.35-7.44 (m, 5H), 7.27 (d, 2H), 6.2 (s, 1H), 6.14 (s, 1H), 5.19(s, 2H), 3.7 (s, 3H).

Step d: Step-c product (2.5 g, 8.21 mmol) was dissolved in ethyl acetate(25 mL) and was taken in Parr hydrogenation bottle followed by palladiumon charcoal (300 mg, 10% Pd) and was hydrogenated at 50 psi for 10 h.The reaction mixture was filtered through celite bed and wasconcentrated to obtain the crude compound (1.6 g, 90%). ¹H NMR (DMSO-d₆,400 MHz): δ 10.08 (s, 1H), 6.93 (d, 2H), 3.70-3.76 (q, 1H), 3.58 (s,3H), 1.34 (d, 3H).

Step e: To a stirred solution of step-d product (2.0 g, 9.25 mmol) inTHF (19 mL), aqueous LiOH solution (1M, 19 mL) was added. The reactionmixture was stirred at ambient temperature for 10 h. TLC showed completeconversion of starting material. The organic solvent was concentratedand water (50 mL) was added to the residue. This aqueous part was washedwith ethyl acetate (30 mL). The aqueous layer was acidified with 1N HClup to pH 2 and extracted with ethyl acetate (3×25 mL). The combinedorganic layer was dried over anhydrous magnesium sulfate andconcentrated to afford desired product (1.7 g, 91%). ¹H NMR (DMSO-d₆,400 MHz): δ 12.3 (bs, 1H), 10.03 (bs, 1H), 6.94 (d, 2H), 3.58-3.61 (q,1H), 1.30 (d, 3H); GCMS (m/z)[M−H]: 201.

6.5 Synthesis of 2-(3-fluoro-4-(trifluoromethyl)phenyl)acetic acid(employed for the synthesis of example compound no. 140)

Step a: In a 50 mL two necked round bottom flask4-bromo-2-fluoro-1-(trifluoromethyl)benzene (0.5 g, 2.05 mmol), ethylchloroacetate (328 mg, 2.67 mmol), and dimethylformamide (4 mL) werecharged. The system was degassed and re filled with argon followed byaddition of Mn (225 mg, 4.1 mmol) and NiBr₂.bipy (62 mg, 0.16 mmol).Finally TFA (4.1 μL) was added and the reaction mixture was degasifiedand refilled with argon. Then it was heated to 65° C. for one hour. TLCshowed (10% ethyl acetate in hexane, R_(f): 0.2) complete conversion ofstarting material. The reaction mixture was diluted with water (50 mL)and HCl (4N, 0.5 mL) and extracted with ethyl acetate (3×40 mL). Thecombined organic part was dried over anhydrous magnesium sulfate andconcentrated under reduced pressure to afford crude material which waspurified by column chromatography (silica gel: 100-200 mesh, eluent: 10%ethyl acetate in hexane) to afford the pure compound (490 mg, 27%). ¹HNMR (DMSO-d₆, 400 MHz): δ 7.54 (t, 1H), 7.15 (d, 2H), 4.16 (q, 2H), 3.64(s, 2H), 1.26 (t, 3H).

Step b: Step-a product (1.48 g, 6 mmol) was dissolved in THF (9 mL).LiOH (9 mL, 1M, 9 mmol) was added to it. The reaction mixture wasstirred at ambient temperature for 2 h. TLC showed (60% ethyl acetate inhexane, R_(f): 0.2) complete conversion of starting material. Thereaction mixture was diluted with water (50 mL) and washed with ethylacetate (2×40 mL). The aqueous part was acidified with 4N HCl (pH˜2) andextracted with in ethyl acetate (3×50 mL). The combined organic layerwas washed with water (50 mL) and brine (50 mL). The combined organicpart was dried over anhydrous magnesium sulfate and concentrated underreduced pressure to afford desired product (1.2 g, 94%). ¹H NMR(DMSO-d₆, 400 MHz): δ 12.58 (s, 1H), 7.72 (t, 1H), 7.43 (d, 1H), 7.32(d, 1H), 3.74 (s, 2H); LCMS [M−H—CO₂]: 177.

6.6 Synthesis of 2-(3-fluoro-4-(trifluoromethyl)phenyl)propanoic acid(employed for the synthesis of example compound no. 141)

Step a: To a stirred solution of4-bromo-2-fluoro-1-(trifluoromethyl)benzene (5 g, 20.57 mmol) in1,4-dioxane (400 mL), bis(pinacolato)diboron (5.2 g, 20.57 mmol) wasadded and deoxygenated twice. Potassium acetate (6.05 g, 61.72 mmol),PdCl₂(PPh₃)₂ (0.43 g, 0.61 mmol) were added to it and againdeoxygenated. The reaction was heated to 100° C. for 12 h. The reactionmixture was filtered through celite bed and evaporated to dryness. Itwas taken in ethyl acetate (200 mL) and was washed with water (2×100mL). The final organic layer was dried over anhydrous magnesium sulfateand evaporated to dryness to afford crude compound, which was purifiedthrough column chromatography (silica: 100-20 mesh, eluent: 5% ethylacetate in hexane) to afford compound (4 g, 67%).

Step b: To a stirred solution of step-a product (4 g, 13.78 mmol) intoluene (50 mL) ethyl 2-(trifluoromethylsulfonyloxy)acrylate (4.1 g,17.92 mmol) was added and deoxygenated twice. Pd(PPh₃)₄ (0.8 g, 0.68mmol) was added and again deoxygenated. 2M sodium carbonate solution (16mL) was added and heated at 60° C. for 10 h. The reaction mixture wasdiluted with water (100 mL) and was extracted with ethyl acetate (2×100mL). The combined organic layer was dried over anhydrous magnesiumsulfate and evaporated to dryness to afford crude compound, which waspurified through column chromatography (silica: 100-200 mesh, eluent: 2%ethyl acetate in hexane) to obtained 1.8 g pure compound (52.6%). ¹H NMR(DMSO-d₆, 400 MHz): δ 7.78 (t, 1H), 7.63 (d, 1H), 7.48 (d, 1H), 6.45 (s,1H), 6.25 (s, 1H), 3.77 (s, 3H).

Step c: Step-b product (1.8 g, 7.62 mmol) in (20 mL) was dissolved inethyl acetate and was taken in Parr hydrogenation bottle followed bypalladium on charcoal (180 mg, 10% Pd) and was hydrogenated at 50 psifor 10 h. The reaction mixture was filtered through celite bed and wasconcentrated to obtain 1.7 g of the crude compound (94%). ¹H NMR(DMSO-d₆, 400 MHz): δ 7.73 (t, 1H), 7.47 (d, 1H), 7.34 (d, 1H), 3.99 (q,1H), 3.61 (s, 3H), 1.42 (d, 3H).

Step d: To a stirred solution of step-c product (1.7 g, 6.79 mmol) inTHF (12 mL), 1M LiOH (12 mL) was added. The reaction mixture was stirredat ambient temperature for 30 minutes. TLC showed complete conversion ofstarting material. The organic solvent was concentrated and water (50mL) was added to the residue. This aqueous part was washed with ethylacetate (30 mL). The aqueous layer was acidified with 1N HCl up to pH 2and extracted with ethyl acetate (3×25 mL). The combined organic layerwas dried over anhydrous magnesium sulfate and evaporated to dryness toobtained compound (1.3 g, 81%). ¹H NMR (DMSO-d₆, 400 MHz): δ 12.59 (bs,1H), 7.73 (t, 1H), 7.45 (d, 1H), 7.34 (d, 1H), 3.86 (q, 1H), 1.40 (d,3H); GCMS (m/z): 236.

6.7 Synthesis of 2-(4-cyclopropyl-3-fluorophenyl)propanoic acid(employed for the synthesis of example compound no. 125)

Step a: To a suspension of potassium iodide (9 g, 94.42 mmol) andisoamyl nitrite (4.89 mL, 36.34 mmol) in acetonitrile (30 mL), asolution of 4-cyclopropyl-3-fluoroaniline hydrochloride (3.4 g, 18.18mmol) in acetonitrile (20 mL) was added at 0° C. After addition reactionmixture was stirred at room temperature for 30 h. Acetonitrile wasevaporated; the obtained residue was diluted with ethyl acetate (250mL), washed with water (2×100 mL), brine solution (50 mL), dried(Na₂SO₄) and concentrated. The obtained crude compound was purified bycolumn chromatography (100-200 mesh Silica gel) using petroleum ether aseluent to afford a yellow liquid (4.1 g, 57.6%).

Step b: A solution of step-a product (1.9 g, 7.25 mmol) andmethyl-2-bromopropanate (2.22 mL, 18.12 mmol) in dimethylformamide (20mL) was degassed with Argon, added 2,2′-bipyridyl (0.113 g, 0.723 mmol),NiBr₂ (158 mg, 0.723 mmol), Mn powder (796 mg, 14.49 mmol), TFA (cat) atroom temperature and the reaction mixture was stirred at 75° C. for 24h. The reaction mixture was cooled to room temperature, diluted withether (200 mL), washed with water (100 mL), brine solution (30 mL),dried (Na₂SO₄), filtered and concentrated. The obtained crude compoundwas purified by column chromatography (100-200 mesh Silica gel) using 5%ethyl acetate in petroleum ether as eluent to afford product as paleyellow liquid (520 mg, 32%).

Step c: To a solution of step-b product (1.2 g, 5.4 mmol) in MeOH (3mL), THF (6 mL), H₂O (6 mL), LiOH.H₂O (900 mg, 21.61 mmol) was added atroom temperature and the reaction mixture stirred at room temperaturefor 3 h. The reaction mixture was concentrated under reduced pressureand residual aqueous layer was diluted with water (75 mL), washed withethyl acetate (50 mL) to remove the impurities. The aqueous layer wasacidified (pH˜4) using 1N aq. HCl (5 mL) and extracted with ethylacetate (2×50 mL). The combined organic layer washed with brine solution(15 ml), dried (Na₂SO₄), filtered and concentrated. The obtained crudecompound was purified by column chromatography (100-200 mesh Silica gel)using 5% ethyl acetate in petroleum ether as eluent to afford compoundtitle compound as pale yellow liquid (650 mg, 58%).

6.8 Synthesis of 2-(3-fluoro-4-((2-methoxyethoxy)methyl)phenyl)propanoicacid (employed for the synthesis of example compound no. 142)

Step a: A suspension of 2-bromoacrylic acid (10 g, 66.66 mmol), BnBr (9mL, 73.72 mmol) and potassium carbonate (18 g, 133.3 mmol). inacetonitrile (100 ml) was stirred at 80° C. for 3 h until completeconsumption. The reaction mixture was filtered and concentrated. Theobtained crude compound was purified by column chromatography (100-200mesh silica gel) using 5% ethyl acetate in petroleum ether as eluent toafford a yellow liquid (10 g, 62.8%).

Step b: To a stirred solution of 4-bromo-2-fluoro benzaldehyde (15 g,79.36 mmol) in MeOH (100 mL) at 0° C. to −5° C., added NaBH₄ (6.0 g,158.73 mmol) in equal portions and stirred at room temperature. Thereaction mixture was diluted with ice cold water (100 mL) andconcentrated under reduced pressure. The obtained aqueous residue wasextracted with ethyl acetate (2×200 mL); the ethyl acetate layer waswashed with brine solution (50 mL), dried over anhydrous NaSO₄, filteredand concentrated to afford a colorless oil (15 g, 99%).

Step c: To a stirred solution of step-b product (10 g, 49.02 mmol) inTHF (250 ml) at 0° C., added 60% NaH (2.93 g, 73.53 mmol) slowly inportions. After addition, the suspension was heated to 50° C. for 30minutes, cooled to room temperature, added 1-bromo-2-methoxy ethane (5ml, 53.92 mmol) and stirred at room temperature for 20 h. The reactionmixture was diluted with ice cold water (100 mL) and concentrated underreduced pressure. The obtained aqueous residue was extracted with ethylacetate (2×150 mL); the combined ethyl acetate layer was washed withbrine solution (50 mL), dried over anhydrous NaSO₄, filtered andconcentrated. The obtained crude compound was purified by columnchromatography (100-200 mesh silica gel) using 5% ethyl acetate inpetroleum ether as eluent to afford product as yellow liquid (6 g, 47%).

Step d: A stirred suspension of step-c product (6 g, 22.8 mmol),bis(pinacolato)diboron (5.8 g, 22.8 mmol), potassium acetate (6.7 g,68.4 mmol) in THF (50 ml) was deoxygenated by purging with a stream ofArgon for 30 minutes, and added Pd (PPh₃)₂Cl₂ (36.5 mg, 0.228 mmol),purging was continued for further 10 minutes. The reaction mixture wasstirred at 100° C. for 1 h. The reaction mixture was concentrated andthe obtained crude compound was purified by column chromatography(100-200 mesh silica gel) using 10% ethyl acetate in petroleum ether aseluent to afford product as a pale yellow oil (5 g, 61.7%).

Step e: A suspension of step-d product (5 g, 16.129 mmol), caesiumcarbonate (15.7 g, 48.38 mmol) in dimethylformamide (50 ml) wasdeoxygenated by purging Argon for 30 minutes at room temperature.Pd(dppf)Cl₂ (657 mg, 0.806 mmol) was added and purging was continued.After 10 minutes, step-a product (4.6 g, 19.35 mmol) was added andstirred at 100° C. for 1 h. The reaction mixture was diluted with ethylacetate (200 mL), filtered through a celite pad, washed with ethylacetate (2×25 mL). The filtrate was washed with water (2×100 mL), brine(50 mL), dried over anhydrous NaSO₄, filtered and concentrated. Theobtained crude compound was purified by column chromatography (100-200mesh silica gel) using 10% ethyl acetate in petroleum ether as eluent toafford product as pale brown oil (1.4 g, 25%).

Step f: A suspension of step-e product (2.8 g, 8.139 mmol), 10% Pd/C(300 mg) in MeOH (20 ml) was hydrogenated (balloon pressure) at roomtemperature for 1 h. The reaction mixture was filtered through celitepad, washed with MeOH (2×15 mL). The combined filtrate was concentratedand the obtained crude compound was purified by column chromatography(100-200 mesh silica gel) using 30% ethyl acetate in petroleum ether aseluent to afford title compound as colorless oil (1.2 g, 57.7%).

6.9 Synthesis of 2-(4-(phenylcarbamoyl)phenyl)propanoic acid (employedfor the synthesis of example compound no. 143)

Step a: A solution of sulfuric acid (118 ml) in water (500 ml) was addedto 4-aminobenzoic acid (150 g, 1094 mmol) and stirred the contents for10 minutes at 0° C. Then a solution of sodium nitrite (98.1 g, 1420mmol, 1.3 eq) in water (500 ml) was added dropwise for 2 h at 0° C. andstirred the contents for 1 hr at the same temperature.

In another round-bottom flask, a solution of sulfuric acid (118 ml) inwater (500 ml) was added to potassium iodide (253.3 g, 1520 mmol, 1.4eq) and the stirred the contents for 15 minutes at 0° C. Above prepareddiazonium solution was added dropwise at 0° C. for 2 h. Overall reactionmixture was allowed to stir for 1 hr at 0° C. and later for another 1 hrat 40° C. Progress of the reaction was monitored by TLC (50% ethylacetate-hexane, R_(f)˜0.1). On completion of the reaction, ice coldwater (500 ml) was added and filtered the contents. Residue was washedwith sodium thio sulfate solution (2×100 ml) and dried to obtain thecrude product as dark brown colored solid (125 g, crude).

Step b: To a solution of the crude step-a product (125 g) in acetone(800 ml), potassium carbonate (103 g, 750 mmol, 1.5 eq) and stirred forsome time at room temperature. DMS (76.2 g, 600 mmol, 1.2 eq) taken inacetone (500 ml) was added dropwise for 30 minutes and the reactionmixture was allowed to stir for 8 h at room temperature. Progress of thereaction was monitored by TLC (50% ethyl acetate-hexane, R_(f)˜0.6). Oncompletion of the reaction, reaction contents were filtered over acelite bed and washed with acetone (100 ml). Filtrate was concentratedunder reduced pressure, residue was taken in dichloromethane (250 ml)and washed with cold water (2×100 ml). Combined organic layer was driedover sodium sulfate, concentrated under reduced pressure and the crudeobtained was purified by column chromatography (silica gel, 5% ethylacetate-hexane) to yield the required product as a white solid (60 g,45%).

Step c: To a solution of step-b product (10 g, 39 mmol) indimethylformamide (DMF) (150 ml, 15 times), 2-chloropropionate (14 g,110 mmol, 3 eq) was added and stirred the contents for 30 minutes whilenitrogen gas is being bubbled. Manganese (4.2 g, 70 mmol, 2 eq) wasadded and stirred the contents for 30 minutes under N₂ atmosphere.NiBr₂.bypridine (1.42 g, 2.6 mmol, 0.07 eq) was added and stirred for 30minutes under N₂ atmosphere. Then a 15-20 drops of TFA was added stirredthe contents for 1 hr. Progress of the reaction was monitored by TLC(10% ethyl acetate-hexane, R_(f)˜0.4). On completion of the reaction,water (30 ml) was added and stirred the contents for 30 minutes. Thenthe contents were filtered and the bed was washed with hexane (2×50 ml).Filtrate was extracted with hexane (4×100 ml) and the obtained aqueouslayer was extracted with hexane (2×50 ml). Combined extract was driedover sodium sulfate, concentrated under reduced pressure and the crudeobtained was purified by column chromatography (silica gel, 3% ethylacetate-hexane) to yield the required product as a red colored liquid (6g, 70%).

Step d: To a stirred solution of step-c product (6 g, 27 mmol) in MeOH(60 ml, 10 times), a solution of sodium hydroxide (2.7 g, 67 mmol, 2.5eq) in water (60 ml, 10 times) was added dropwise at room temperature.Overall reaction mixture was allowed to stir for 3 h at roomtemperature. Progress of the reaction was monitored by TLC (50% ethylacetate-hexane, R_(f)˜0.1). As the reaction not moved completely,reaction contents were allowed to stir for another 5 h. Again TLC waschecked and confirmed that the starting material was disappeared.Methanol was distilled off completely and the residue was cooled to 0°C. Then the contents were acidified at a pH˜2 with 6N HCl solution andsolid thrown out was filtered. Solid obtained was dissolved in ethylacetate (100 ml), dried over sodium sulfate and concentrated underreduced pressure to yield the required product as an off white solid(4.5 g, 86%).

Step d: To a stirred solution of step-d product (2.5 g, 12 mmol) in dryMeOH (25 ml, 10 times), TMS Chloride (1.39 g (1.64 ml), 12 mmol, 1 eq)was added dropwise and the reaction mixture was allowed to stir for 2 hat room temperature. Progress of the reaction was monitored by TLC (50%ethyl acetate-hexane, R_(f)˜0.4). On completion of the reaction, MeOHwas distilled off completely under reduced pressure. Residue was takenin dichloromethane (50 ml) and washed with sodium bicarbonate solution(2×50 ml). Aqueous layer was washed with ethyl acetate (50 ml) followedby hexane (50 ml). Then the aqueous layer was cooled to 0° C., acidifiedwith to a pH˜2 6N HCl solution and the solid thrown out was filtered.Solid obtained was dissolved in ethyl acetate (100 ml), dried oversodium sulfate and concentrated under reduced pressure to yield therequired product as an off white solid (1.54 g, 61%).

Step f-g: To a stirred solution of step-e product (2.3 g, 10 mmol) indichloromethane (23 ml), oxalyl chloride (2.08 g (1.44 ml), 16 mmol, 1.5eq) followed by catalytic amount of dimethylformamide were added at roomtemperature. Reaction contents were stirred for 20 minutes at roomtemperature. Progress of the reaction was monitored by TLC (5% ethylacetate-hexane, R_(f)˜0.7). As the reaction not moved completely,reaction contents were heated to 40° C. and stirred for 1 hr at the sametemperature. Again TLC was checked and confirmed that the startingmaterial was disappeared. Dichloromethane was distilled off completelyunder reduced pressure. In another round-bottom flask, TEA(triethylamine) (3.2 g (2.5 ml), 25 mmol, 2.5 eq) was added to asolution of aniline (0.83 g, 9 mmol) in dichloromethane (10 ml) andstirred the contents for 15 minutes at 0° C. Then the above preparedacid chloride was taken in dichloromethane (13 ml) and added dropwise at0° C. and the overall reaction mixture was allowed to stir for 1 hr at0° C. Progress of the reaction was monitored by TLC (5% ethylacetate-hexane, R_(f)˜0.3). On completion of the reaction, water (10 ml)was added and the layers formed were separated out. Organic layer wasdried over sodium sulfate and concentrated under reduced pressure toyield the required product as an off white solid (3 g, 96%).

Step h: To a solution of step-g product (3 g, 10 mmol) in THF (30 ml, 10times), water (30 ml, 10 times) was added and the reaction contents werestirred for 15 minutes at room temperature. Then LiOH (0.5 g, 21 mmol, 2eq) was added and the overall reaction mixture was allowed to stir for 5h at room temperature. Progress of the reaction was monitored by TLC (5%ethyl acetate-hexane, R_(f)˜0.1). On completion of the reaction, THF wasdistilled off completely under reduced pressure. Aqueous layer waswashed with ethyl acetate (50 ml) followed by hexane (50 ml). Then theaqueous layer was cooled to 0° C., acidified to a pH˜2 with 6N HClsolution and the solid thrown out was filtered. Solid obtained wasdissolved in ethyl acetate (100 ml), dried over sodium sulfate andconcentrated under reduced pressure to yield the required product as anoff white solid (2.15 g, 75%).

6.10 General scheme for the synthesis of2-(4-sulphonamidophenyl)propanoic acids

In step j10 the nitro-substituted phenyl J-VII can be reacted to formthe compound J-VIII by means of methods known to the person skilled inthe art, for example in a substitution reaction using a singlyhalogenated, preferably singly chlorinated or brominated ester J-VI, ifappropriate in the presence of a base.

If appropriate, the singly halogenated, preferably singly chlorinatedester J-VI, for which R^(5b)≠H, can be prepared in a preceding step k06from a dihalogen carboxylic acid ester K-V, wherein halogen ispreferably Br or Cl, by means of methods known to the person skilled inthe art, in order in this way to introduce the residue R^(5b) (R^(5b)≠H)into J-VI.

If, in step j10, use is made of compounds J-VI for which R^(5a) andR^(5b) are each H or for which the substituent is R^(5b)═H, thenfunctional groups in the positions R^(5a) and R^(5b) or the positionR^(5b) can each be introduced in the synthesis sequence at a later pointin time, for example after step j10 and before step j11. In this case,compounds J-VIII, in which R^(5b)═H, or compounds J-VIII, in whichR^(5a) and R^(5b) each ═H, are reacted in a further step j10a and j10brespectively, which are each carried out between the steps j10 and j11,to form compounds J-VIII-a, in which R^(5b)≠H, or compounds J-VIII-b, inwhich R^(5a) and R^(5b) each #H. The compounds J-VIII-a and J-VIII-b cansubsequently be reacted further in step j 1.

In step j11 the nitro function of the compound J-VIII (or J-VIII-a orJ-VIII-b) can be converted into an aniline derivative J-IX by means ofmethods known to the person skilled in the art, such as for example byhydrogenation with hydrogen or by reduction by acidic metal saltsolutions.

In step j12 the aniline compound J-IX can be reacted to form thecompound J-X by means of methods known to the person skilled in the art,for example using a halogenated, preferably chlorinated sulphonylcompound of formula R⁰—S(═O)₂—Hal, preferably R⁰—S(═O)₂—Cl, ifappropriate in the presence of a base.

J-X can be reacted to form the compound J-XI immediately in step j13using an ester cleavage known to the person skilled in the art, forexample using a base or an acid. However, alternatively, the sulphonylamino function of J-X can in step j14 first be N-substituted to form thecompound J-XII by means of methods known to the person skilled in theart, for example using a halide R⁰—Hal, preferably an iodide R⁰—I, andthe aforementioned ester cleavage to form J-XIII can then subsequentlybe carried out in step j15.

The methods with which the person skilled in the art is familiar forcarrying out the reaction steps j10 to j15 and also k06 may be inferredfrom the standard works on Organic Chemistry such as, for example, J.March, Advanced Organic Chemistry, Wiley & Sons, 6th edition, 2007; F.A. Carey, R. J. Sundberg, Advanced Organic Chemistry, Parts A and B,Springer, 5th edition, 2007); team of authors, Compendium of OrganicSynthetic Methods, Wiley & Sons. In addition, further methods and alsoliterature references can be issued by the common databases such as, forexample, the Reaxys® database of Elsevier, Amsterdam, NL or theSciFinder® database of the American Chemical Society, Washington, US.

6.10.1 Synthesis of 2-(3-fluoro-4-(sulphonamido)phenyl)propanoic acids

Step j10: Under a nitrogen atmosphere, 3 equivalents of potassium tert.butyloxide are slurried in DMF and cooled to −40° C. A mixture ofo-fluoronitrobenzene (J-VII) (1 equivalent) and ethyl-2-chloropropionate(J-VI) (1.2 equivalent) is then added while maintaining this temperatureand the mixture is stirred for 10 minutes. The reaction mixture isdiluted with acetic acid and with water at −40° C. The aqueous phase isthen repeatedly extracted with 20% EE in hexane, the combined organicphases are washed with water and sat. aq. NaCl sol. and dried overmagnesium sulphate. The concentrated organic phase is purified by columnchromatography (SiO₂, 10% EE/hexane), as a result of which the productJ-VIII is obtained.

Step j11: A suspension of J-VIII (1 equivalent) and palladium onactivated carbon (10% Pd) in EtOH is hydrogenated for 1 h under ahydrogen atmosphere. The suspension is removed by filtration,concentrated under vacuum and purified by column chromatography (SiO₂,EE/hexane) and J-IX is in this way obtained.

Step j12: J-IX (1 equivalent) is placed in dichloromethane and pyridineand cooled to 0° C. Compounds of general formula Cl—S(═O)₂—R⁰ (1.5equivalents) are added dropwise at 0° C. and the reaction mixture isstirred for 2 h at room temperature. After recooling of the mixture to0° C., the mixture is acidified to pH 3 using 4 N aq. HCl. The organicphase is repeatedly extracted with dichloromethane. The combined organicphases are washed with water and sat. aq. NaCl sol., dried overmagnesium sulphate and concentrated to dryness. The purification (SiO₂,EE/hexane) by column chromatography produces the desired product J-X.

Step j13: 1 equivalent of J-X is dissolved in a 2:1 mix of THF/water andstirred for 15 minutes. 3 equivalents of LiOH, which is also dissolvedin a 2:1 THF/water mix, are added to this solution and the suspension isstirred for 2 h at 45° C. While cooling, the aqueous phase is set to pH1 using 4 N aq. HCl and repeatedly extracted with dichloromethane. Thecombined organic phases are dried over magnesium sulphate andconcentrated under reduced pressure and the product J-XI is in this wayobtained.

6.10.2 Synthesis of2-(3,5-difluoro-4-(methylsulphonamido)phenyl)propanoic acid

Step j10: KOtBu (31.85 mmol, 3.57 g) was dissolved in DMF (30 ml) andcooled to −45° C. A mix of ethyl-2-chloropropionate (15.9 mmol, 2 ml)and 1,3-difluoro-2-nitrobenzene (15.7 mmol, 2.5 g) was slowly addeddropwise to the solution, which was kept at −40° C., and after additionthe mixture was stirred for a further 1 h. For working up, the reactionmix was set to pH 4 using 16% HCl and diluted with water (150 ml). Themix was extracted with EE (3×50 ml), the combined organic phases werewashed with water (50 ml) and sat. NaCl solution (2×50 ml) and driedover magnesium sulphate. After removal of the solvent under vacuum, theproduct was obtained as an oil (4.12 g, 99% yield).

Step j11: The difluoronitrophenylpropanoate (10 mmol, 2.59 g) wasdissolved in EtOH/EE (200 ml, 1: 1) and hydrogenated in an H-cube (1bar, 25° C., 1 ml/min, 0.25 mol/L). After removal of the solvent undervacuum, the difluoroaminopropionate could be obtained as an oil (2.27 g,99% yield).

Step j12: The difluoroaminophenylpropanoate (5 mmol, 1.15 g) wasdissolved in pyridine (4 ml), cooled to 0° C. under a protective gasatmosphere and mixed dropwise with methanesulphonyl chloride (7.5 mmol,582 μL). After stirring for one hour at 0° C., the reaction mixture wasmixed with water (25 ml) while being cooled with ice, set to pH 1 using16% HCl and extracted with dichloromethane (2×50 ml). The organic phaseswere combined, dried over magnesium sulphate and the solvent was removedunder vacuum. The purification (SiO₂, cyclohexane/EE 2:1) of the residueby column chromatography produced 0.458 g of product (28% yield).

Step j13: The product of the mesylation (1.46 mmol, 0.45 g) wasdissolved in THF/water (5 ml, 2:1), LiOH (4.39 mmol, 0.105 g) was addedand the mixture was refluxed for 12 h. Water (25 ml) and diethyl ether(25 ml) were added to the reaction mix. After phase separation, theaqueous phase was acidified to pH 2 using HCl and extracted withdichloromethane (3×25 ml). The combined organic phases were dried overmagnesium sulphate and the solvent was removed under vacuum. The productwas obtained as a white solid (0.402 g, 98% yield).

6.10.3 Synthesis of 2-(3-fluoro-4(methysulphonylamino)phenyl)propanoicacid

Step j10: Potassium tert. butyloxide (1,000 g, 8.93 mol) was placedunder a nitrogen atmosphere and the slurry obtained after addition von 4l of DMF was cooled to −40° C. A mixture of o-fluoronitrobenzene (420 g,2.97 mol) and ethyl-2-chloropropionate (488 g, 3.57 mol) was added whilemaintaining this temperature and stirred for 10 minutes. The reactionmixture was quenched with HOAc at −40° C. and diluted with 30 l ofwater. The liquid phase was repeatedly extracted with 20% EE in hexane(3×15 l), the combined organic phases were washed with water (4×10 l)and sat. aq. NaCl (10 l) and dried over MgSO4. The concentrated organicphase was purified by column chromatography (silica gel. 100-200 mesh,eluent: 10% EE in hexane) and produced 483 g of the nitroester (67.3%).¹H NMR (CDCl₃, 400 MHz): δ [ppm] 8.01 (t, 1H), 7.21-7.26 (m, 2H),4.06-4.19 (m, 2H), 3.76 (q, 1H), 1.50 (d, 3H), 1.22 (t, 3H). HPLC: 97%.

Step j11: The nitroester (250 g, 0.248 mol) and MeOH (1.1 l), followedby palladium on activated carbon (10 g, 10% Pd), were introduced in a 2l Parr hydrogenator under a nitrogen atmosphere, flushed with nitrogenand hydrogenated at 45 psi for 3 h at room temperature. The reaction mixwas removed by filtration and washed with 1 l of MeOH. The brown liquidobtained after concentration of the organic phase was purified by columnchromatography (silica gel: 100-200 mesh, eluent: 10% EE in hexane).118.8 g of the amino ester (54.24%) were obtained. ¹H NMR (DMSO-d₆, 400MHz): δ [ppm] 6.88 (dd, 1H), 6.78 (dd, 1H), 6.69 (t, 1H), 3.96-4.06 (m,2H), 3.55-3.60 (q, 1H), 1.29 (d, 3H), 1.15 (t, 3H). Qualitative HPLC:99%.

Step j12: The amino ester (110 g, 0.52 mol) was placed in 900 ml ofdichloromethane and pyridine (63 ml, 0.78 mol) and cooled to 0° C.Methanesulphonyl chloride (44.4 ml, 0.57 mol) was added dropwise at 0°C. and the reaction mixture was stirred for 2 h at room temperature.After recooling of the mixture to 0° C., the mixture was acidified to pH3 using 4 N HCl. The organic phase was repeatedly extracted withdichloromethane (3×600 ml). The combined organic phases were washed withwater (2×1 l) and sat. aq. NaCl sol. (1×1 l), dried over MgSO₄ andconcentrated to dryness. The purification by column chromatography(silica gel: 100-200 mesh, eluent; 15% EE in hexane) produced 85.8 g ofproduct (56.9%). ¹H NMR (DMSO-d₆, 400 MHz): δ [ppm] 7.33 (t, 1H), 7.21(d, 1H), 7.10 (dd, 1H), 4.01-4.10 (m, 2H), 3.80 (q, 1H), 3.01 (s, 3H),1.37 (d, 3H), 1.13 (t, 3H). Qualitative HPLC: 99%.

Step j13 is carried out as described under 6.10.2.

6.10.4 Synthesis ofN-methyl-2-(3-fluoro-(4-methysulphonylamino)phenyl)propanoic acid

Steps j10 to j12 are carried out as described under 6.10.3.

Step j14: 1 equivalent of ethyl2-[3-fluoro-4(methylsulphonylamino)phenyl]propanoate was added to asuspension of 1.25 equivalents of NaH (60%) in DMF and the mixture wasstirred for 30 minutes at room temperature. 3.75 equivalents of methyliodide were added portionwise to this reaction mixture and the mixturewas stirred for 1.5 h at 100° C. and slowly cooled to room temperature.After the addition of water, the reaction mix was extracted twice withEE, the combined organic phases were repeatedly washed with sat. aq.NaCl sol., dried over MgSO₄ and concentrated. The crude product J-XI wasfurther processed immediately in step j15.

Step j15: 1 equivalent of J-XI was dissolved in a 2:1 THF/water mix andstirred for 15 minutes. 3 equivalents of LiOH, which is also dissolvedin a 2:1 THF/water mix, are added to this solution and the mixture isstirred for 2 h at 45° C. While cooling, the aqueous phase is set to pH1 using 4 N HCl and repeatedly extracted with dichloromethane. Thecombined organic phases are dried over MgSO₄ and concentrated underreduced pressure.

6.11 Synthesis of further2-(3-fluoro-(4-methysulphonylamido)phenyl)-propanoic and acetic acids6.11.1 Acids Wherein R^(5b)═C₁₋₁₀ Alkyl Preferably CH₃, CH₂—CH₃,CH₂—CH₂—CH₃

The substituent R^(5b) is introduced in a reaction step j10a interveningbetween j10 and j11 as in scheme 2.

Steps j10 and also j11 to j13 are carried out as described above.

Step j10a: 0.75 equivalents of alkyl iodide (R^(5b)—I) are slowly addeddropwise to a solution of J-VIII (1 equivalent) and NaH (0.6equivalents) in DMF at 0° C. and the reaction batch is stirred forapprox. 10 minutes. Afterwards the reaction mixture is quenched with 1 NHCl sol., diluted with water and repeatedly extracted with diethylether. The combined organic phases are washed with water and sat. aq.NaCl sol., dried over MgSO₄ and concentrated under vacuum. A furtherpurification of the crude product can be carried out by columnchromatography (silica gel: 100-200 mesh, eluent: 10-20% EE in hexane),as a result of which the product J-VIII-a is obtained.

6.11.2 Acids in which R^(5a) and R^(5b) Form Together with the CarbonAtom Connecting them a C₃₋₁₀ Cycloalkyl

The substituents R^(5a) and R^(5b) are introduced in a reaction stepj10b intervening between j10 and j11 as in scheme 2.

Step j10:

At 0° C. a mixture of 3-fluorophenyl acetate (1 equivalent) andsulphuric acid (0.261 equivalents) is added dropwise to a solution ofnitric acid (1 equivalent) and the mixture is stirred for 2 h. Thereaction mix is diluted with iced water and repeatedly extracted withEE. The combined organic phases are washed with water, concentratedunder vacuum and purified by column chromatography (eluent: EE/hexane)and J-VIII is in this way obtained.

Step j10b:

NaH (10 equivalents) is slowly added to the J-VIII (1 equivalent)dissolved in dry THF, the mixture is stirred for 10 minutes and thecorresponding 1,1-dihalogenalkyl compound, preferably a dibromoalkylcompound (5 equivalents), is then added. Within 30 minutes the mixtureis heated to room temperature heated and quenched with sat. aq. NH₄Clsol. After aqueous working up, the crude product obtained is purified byflash chromatography (eluent: EE/hexane) and J-VIII-b is in this wayobtained.

Steps j11 to j13 are carried out as described hereinbefore.

6.11.3 Synthesis of2-cyclohexyl-2-(3-fluoro-4-(methylsulphonamido)phenyl)acetic acid

Step k06: Ethyl 2-chloro-2-cyclohexyl acetate

170 ml of dry THF were mixed with 100 ml of 1 M BH₃-THF complex (100mmol) at room temperature under a nitrogen atmosphere. Within 5 minutes12.3 ml of cis-1,5-cyclooctadiene (100 mmol) were added dropwise to thismix, wherein the temperature rose to 45° C. The reaction mix was boiledto reflux for 1.5 h, recooled to 45° C., mixed with 10.1 ml ofcyclohexene (100 mmol) and stirred for a further 2 h at 45° C. Aftercooling of the reaction batch in an ice bath, 12.2 ml of ethyldichloroacetate (100 mmol) were added in 50 ml of tert. butanol, themixture was stirred for 15 minutes and within a further 15 minutes 1 Mpotassium tert. butylate (100 mmol, 100 ml) was added dropwise. Thereaction mix was stirred for a further 15 minutes, mixed with 33 ml of 3M sodium acetate sol. (100 mmol) and 22.5 ml of 30% H₂O₂ (750 mmol) werecarefully added dropwise. The mix was stirred for 30 minutes at roomtemperature and subsequently salted out with NaCl; the organic phase wasdried over MgSO₄ and the solvent was removed under reduced pressure.After washing of the solid residue with tert. BME, cyclohexane tert. BME(9:1), tert. BME and EE, 7.6 g (37.4%) of product could be obtained.

Step j10: Ethyl 2-cyclohexyl-2-(3-fluoro-4-nitrophenyl)acetate

8.2 g of potassium tert. butylate were dissolved in 70 ml of DMF andcooled to −45° C. For this purpose, a mix of ethyl2-chloro-2-cyclohexylacetate (36.6 mmol, 7.5 g) and1-fluoro-2-nitrobenzene (36.6 mmol, 3.9 ml) was carefully added dropwiseand stirred for a further 20 minutes. The reaction mix was set to pH 4using 16% HCl, diluted with 25 ml of water and extracted with EE (3×50ml). Once combined, the organic phases were washed with water and sat.aq. NaCl sol., dried over MgSO₄ and concentrated under vacuum. Theresidue obtained was purified by column chromatography (silica gel: mesh100-200, eluent: 10% EE in cyclohexane) and produced 5.5 g (49%) ofproduct.

Step j11: Ethyl 2-(4-amino-3-fluorophenyl)-2-cyclohexylacetate

The ethyl 2-cyclohexyl-2-(3-fluoro-4-nitrophenyl)acetate was dissolvedin a 1:1 mix of EtOH and EE (420 ml) and hydrogenated in an H-cube (1bar, 25° C., 1 ml/min and 0.25 mol/L). After removal of the solvent anddrying, 5 g (quantitative turnover) of product could be obtained.

Step j12: Ethyl2-cyclohexyl-2-(3-fluoro-4-(methylsulphonamido)phenyl)acetate

The amine compound (5 g, 17.9 mmol) was dissolved in 15 ml of pyridine,cooled to 0° C. under a nitrogen atmosphere and mixed with 2 ml ofmethanesulphonyl chloride (26.8 mmol) and stirred for a further 1 h at0° C. The reaction mix was mixed with 15 ml of water while being cooledwith ice and set to pH 1 using 16% HCl. After extraction of the mix withdichloromethane (3×50 ml), the organic phases were combined, dried overMgSO₄ and concentrated under vacuum. The crude product was purified bycolumn chromatography (silica gel: 100-200 mesh, eluent: 50% EE incyclohexane), producing 5.4 g (85.4%) of product.

Step j13: 2-cyclohexyl-2-(3-fluoro-4-(methylsulphonamido)phenyl)aceticacid

The phenylacetate (15.2 mmol, 5.4 g) was dissolved in a mix of 30 ml ofTHF and 15 ml of water, mixed with 1.09 g of LiOH (45.7 mmol) and boiledto reflux for 6 h and stirred for a further 12 h at room temperature. 15ml of water were added to the reaction mix and the phases wereseparated. The aqueous phase was acidified using HCl and repeatedlyextracted with dichloromethane (3×50 ml). The combined organic phaseswere dried over MgSO₄, concentrated and the residue obtained waspurified by means of column chromatography (silica gel: 100-200 mesh,eluent: 50% EE in cyclohexane). Yield 1.05 g (21%).

6.11.4 Synthesis of2-(3-fluoro-4-(methylsulphonamido)phenyl)-2-phenylacetic acid

Step k06: Ethyl 2-chloro-2-phenylacetate

Chlorophenyl acetyl chloride (53 mmol, 7.6 ml) was added dropwise to asolution of triethylamine (63.5 mmol, 8.7 ml) in methanol at 0° C. andthe mixture was subsequently stirred for 3.5 h at room temperature. Thereaction mix was then placed in 100 ml of water and repeatedly extractedwith EE (3×100 ml). Once combined, the organic phases were dried overMgSO4, concentrated under vacuum and 8.76 g (83.4%) of product wasobtained.

Step j10: Ethyl 2-(3-fluoro-4-nitrophenyl)-2-phenylacetate

9.8 g of potassium tert. butylate were dissolved in 90 ml of DMF andcooled to −45° C. For this purpose, a mix of ethyl2-chloro-2-phenylacetate (43.8 mmol, 8.7 g) and 1-fluoro-2-nitrobenzene(43.8 mmol, 4.6 ml) was carefully added dropwise and the mixture wasstirred for a further 20 minutes. The reaction mix was set to pH 4 using16% HCl, diluted with 25 ml of water and extracted with EE (3×50 ml).Once combined, the organic phases were washed with water and sat. aq.NaCl sol., dried over MgSO₄ and concentrated under vacuum. The residueobtained was purified by column chromatography (silica gel: mesh100-200, eluent: 10% EE in cyclohexane) and produced 5.9 g (44.9%) ofproduct.

Step j11: Ethyl 2-(4-amino-3-fluorophenyl)-2-phenylacetate

The ethyl 2-phenyl-2-(3-fluoro-4-nitrophenyl)acetate was dissolved in a1:1 mix of EtOH and EE (465 ml) and hydrogenated in an H-cube (1 bar,25° C., 1 ml/min and 0.25 mol/L). After removal of the solvent anddrying, 5.2 g (97.5%) of product could be obtained.

Step j12: Ethyl2-phenyl-2-(3-fluoro-4-(methylsulphonamido)phenyl)acetate

The amine compound (5.2 g, 19 mmol) was dissolved in 15 ml of pyridine,cooled to 0° C. under a nitrogen atmosphere and mixed with 2.2 ml ofmethanesulphonyl chloride (28.5 mmol) and stirred for a further 1 h at0° C. The reaction mix was mixed with 15 ml of water while being cooledwith ice and set to pH 1 using 16% HCl. After extraction of the mix withdichloromethane (3×50 ml), the organic phases were combined, dried overMgSO₄ and concentrated under vacuum. The crude product was purified bycolumn chromatography (silica gel: 100-200 mesh, eluent: 50% EE incyclohexane), producing 5.8 g (87%) of product.

Step j13: 2-phenyl-2-(3-fluoro-4-(methylsulphonamido)phenyl)acetic acid

The phenylacetate (16.5 mmol, 5.8 g) was dissolved in a mix of 32 ml ofTHF and 16 ml of water, mixed with 1.18 g of LiOH (49.5 mmol) and boiledto reflux for 15 h. 15 ml of water were added to the reaction mix andthe phases were separated. The aqueous phase was acidified using HCl andrepeatedly extracted with dichloromethane (3×50 ml). The combinedorganic phases were dried over MgSO4, concentrated and the residueobtained was purified by means of column chromatography (silica gel:100-200 mesh, eluent: 50% EE in cyclohexane). Yield 3.3 g (61.3%).

6.11.5 Synthesis of2-(3-fluoro-4-(methylsulfonamido)phenyl)-2-(3-fluorophenyl)acetic acid(employed for the synthesis of example compound No. 66)

Step a: 2-(3-fluorophenyl)-2-hydroxyacetic acid (12 g, 70.5 mmol), wasdissolved in THF (120 mL). Thionyl chloride (10 g, 84.6 mmol) was addedto it. Catalytic amount of dimethylformamide (1 mL) was added to thereaction mixture. The reaction mixture was stirred at ambienttemperature for overnight. The organic solvent was removed under reducedpressure; the residue was diluted with water (200 mL) and extracted withdichloromethane (2×200 mL). The combined organic layer was dried overanhydrous magnesium sulfate and concentrated under reduced pressure toafford 12 g crude compound.

Step b: The crude step-a product (12 g) was dissolved in benzene (240mL). EtOH (120 mL) and sulphuric acid (2 mL) was added to it. Thereaction mixture was refluxed for 4 h using Dean stark apparatus. TLC(5% ethyl acetate-Hexane, R_(f)=0.7) showed complete consumption ofstarting material. The organic solvent was removed under reducedpressure and the residue was diluted with water (200 mL). The aqueouspart was extracted with 20% ethyl acetate in hexane (3×200 mL). Thecombined organic layer was dried over anhydrous magnesium sulfate andconcentrated under reduced pressure to afford a yellow residue, whichwas purified by column chromatography (silica gel: 100-200 mesh, eluent:2% ethyl acetate in hexane) to afford a light yellow liquid compound(8.2 g, 59.5%).

Step c: To a stirred suspension of potassium tertiary butoxide (8.5 g,75.75 mmol) in dimethylformamide (50 mL), a mixture of step-b product(8.2 g, 38 mmol) and 1-fluoro-2-nitrobenzene (5.34 g, 38 mmol) indimethylformamide (30 mL) was added at −30° C. The reaction mixture wasstirred for 30 minutes at the same temperature. TLC (10% ethylacetate-Hexane, R_(f)=0.6) showed complete consumption of startingmaterial. Reaction mixture was diluted with water (800 mL) and extractedwith 20% ethyl acetate in hexane (3×200 mL). Then the organic layer wasdried over anhydrous magnesium sulfate. The removal of organic solventunder reduced pressure afforded a brown liquid compound, which waspurified by column chromatography (silica gel: 100-200 mesh, eluent: 2%ethyl acetate in hexane) to afford a light brown liquid compound (3.2 g,26%)

Step d: In a 250 mL round-bottom flask step-c product (3.2 g, 10 mmol)was dissolved in ethyl acetate (50 mL). Palladium on charcoal (150 mg,10% Pd) was added under nitrogen atmosphere. It was stirred underatmospheric hydrogen pressure for 12 h. TLC (20% ethyl acetate inhexane, R_(f)=0.3) showed complete conversion of starting material. Thereaction mixture was filtered over celite bed and the bed was washedwith ethyl acetate (3×50 mL). The organic layer was concentrated toafford a yellow residue, which was purified through columnchromatography (silica gel: 100-200 mesh, eluent: 10% ethyl acetate inhexane) to afford the pure amine compound (2.3 g, 79%).

Step e: Step-d product (2.3 g, 7.8 mmol) was dissolved indichloromethane (35 mL). Pyridine (1.9 mL, 23.4 mmol) was added to it.Methanesulphonyl chloride (1.1 g, 9.4 mmol) was added dropwise to thereaction mixture at 0° C. and stirred for 16 h at ambient temperature.TLC (20% ethyl acetate in hexane, R_(f)=0.2) showed complete consumptionof starting material. The reaction mixture was diluted withdichloromethane (100 mL) and washed with water (3×50 mL). The organiclayer was then dried over anhydrous magnesium sulfate and concentratedto afford a solid compound, which was purified through columnchromatography (silica gel: 100-200 mesh, eluent: 15% ethyl acetate inhexane) to afford the pure compound (2.8 g, 96%). ¹H NMR (CDCl₃, 400MHz): δ 7.55 (t, 1H), 7.30-7.35 (q, 1H), 6.98-7.18 (m, 5H), 6.50 (s,1H), 4.21-4.27 (q, 2H), 3.04 (s, 3H), 1.28 (t, 3H).

Step f: Step-e product (2.8 g, 7.5 mmol), was dissolved in THF (30 mL).Aqueous LiOH solution (1M, 23 mL, 23 mmol) was added dropwise at 00° C.to it. The reaction mixture was then stirred at ambient temperature for16 h. TLC (30% ethyl acetate-Hexane, R_(f)=0.05) showed completeconsumption of starting material. The solvent was removed under reducedpressure and residue was diluted with water (70 mL). The aqueous layerwas washed with ethyl acetate (70 mL) and aqueous part was acidifiedwith 2N HCl up to pH=3-4. The acidified aqueous part was then extractedwith ethyl acetate (3×150 mL). The combine organic part was dried overanhydrous magnesium sulfate and concentrated under reduced pressure toafford a white solid compound. (1.8 g, 70%). ¹H NMR (DMSO-d₆, 400 MHz):δ 12.99 (bs, 1H), 9.58 (s, 1H), 7.08-7.41 (m, 7H), 5.16 (s, 1H), 3.01(s, 3H); Mass (M+1): 342.

6.11.6 Synthesis of2-(3-fluoro-4-(methylsulfonamido)phenyl)-2-p-tolylacetic acid (employedfor the synthesis of example compound No. 68)

Step a: Sodium cyanide (7.3 g, 149.8 mmol) was dissolved in water (30mL) and ammonium chloride (13.3 g, 249.6 mmol) was added to it.4-Methylbenzaldehyde (15 g, 124.8 mmol) in MeOH (25 mL) was added to thereaction mixture and stirred it at ambient temperature for two days. TLC(5% ethyl acetate-Hexane, R_(f)=0.4) showed complete consumption ofstarting material. Water (100 mL) and benzene (100 mL) was added to thereaction mixture and stirred for 10 minutes. The separated organic layerwas dried over anhydrous magnesium sulfate and concentrated underreduced pressure to afford a yellow liquid compound (17 g, crude).

Step b: The crude step-a product (17 g) was dissolved 6N HCl (136 mL)and refluxed for 20 h. HCl was removed under reduced pressure. Theresidue was diluted with EtOH (2×200 mL) and concentrated under reducedpressure. Finally ethyl acetate (250 mL) was added and stirred at 70° C.for 1 hour. A solid came out upon cooling and it was filtered throughglass-sintered funnel to afford yellow crystalline solid compound (15 g,crude).

Step c: Step-b product (15 g, 74.4 mmol) was dissolved in HCl (300 mL)and it was cooled to −5° C. Sodium nitrite solution (9.75 g, 141.3 mmol)in water (45 mL) was added dropwise over the period of 30 minutes. Aftercomplete addition, reaction mixture was stirred at ambient temperaturefor 3 h. TLC (in ethyl acetate R_(f)=0.3) showed complete consumption ofstarting material. The aqueous part was extracted in ethyl acetate(3×250 mL). The organic layer was washed with water (2×200 mL) andfinally with brine (200 mL). The washed organic layer was dried overanhydrous magnesium sulfate and concentrated under reduced pressure toafford a yellow solid (12.5 g, crude).

Step d: Step-c product (10 g, 54 mmol) was dissolved in benzene (200mL). EtOH (100 mL) and sulphuric acid (2 mL) was added to it. Thereaction mixture was refluxed for 4 h. TLC (in 5% ethyl acetate-Hexane,R_(f)=0.7) showed complete consumption of starting material. The organicsolvent was removed under reduced pressure and the residue was dilutedwith water (200 mL). The aqueous part was extracted with 20% ethylacetate in hexane (3×200 mL). The combined organic layer was dried overanhydrous magnesium sulfate and concentrated under reduced pressure toafford a yellow residue, which was purified by column chromatography(silica gel: 100-200 mesh, eluent: 2% ethyl acetate in hexane) to afforda light yellow liquid compound (10 g, 87%).

Step e: To a stirred suspension of potassium tertiary butoxide (10.6 g,94 mmol) in dimethylformamide (60 mL), a mixture of step-d product (10g, 47 mmol) and 1-fluoro-2-nitrobenzene (6.6 g, 47 mmol) indimethylformamide (40 mL) was added at −30° C. The reaction mixture wasstirred for 30 minutes at the same temperature. TLC (10% ethylacetate-Hexane, R_(f)=0.6) showed complete consumption of startingmaterial. Reaction mixture was diluted with water (1 L) and extractedwith 20% ethyl acetate in hexane (3×250 mL). Then the organic layer wasdried over anhydrous magnesium sulfate. The removal of organic solventunder reduced pressure afforded a yellowish compound, which was purifiedby column chromatography (silica gel: 100-200 mesh, eluent: 2% ethylacetate in hexane) to afford a yellow liquid compound (10.4 g, 68%). ¹HNMR (CDCl₃, 400 MHz): δ 8.12 (t, 1H), 7.55 (dd, 1H), 7.37 (dd, 1H),7.16-7.23 (m, 4H), 5.38 (s, 1H), 4.13-4.18 (m, 2H), 2.27 (s, 3H), 1.16(t, 3H).

Step f: In a 500 mL round-bottom flask step-e product (10.4 g, 33 mmol)was dissolved in ethyl acetate (150 mL). Palladium on charcoal (520 mg,10% Pd) was added under nitrogen atmosphere. It was stirred underatmospheric hydrogen pressure for 12 h. TLC (20% ethyl acetate inhexane, R_(f)=0.3) showed complete conversion of starting material. Thereaction mixture was filtered over celite bed and the bed was washedwith ethyl acetate (3×100 mL). The organic layer was concentrated toafford a yellow residue, which was purified through columnchromatography (silica gel: 100-200 mesh, eluent: 10% ethyl acetate inhexane) to afford the pure amine compound (8 g, 85%). ¹H NMR (CDCl₃, 400MHz): δ 7.10-7.15 (m, 4H), 6.89 (dd, 1H), 6.80 (dd, 1H), 6.68 (t, 1H),5.09 (s, 1H), 4.92 (s, 1H), 4.07-4.12 (m, 2H), 2.25 (s, 3H), 1.15 (t,3H).

Step g: Step-f product (8 g, 27.8 mmol) was dissolved in dichloromethane(120 mL). Pyridine (6.7 mL, 83.5 mmol) was added to it.Methanesulphonylchloride (3.8 g, 33.4 mmol) was added dropwise to thereaction mixture at 0° C. and stirred for 16 h at ambient temperature.TLC (20% ethyl acetate in hexane, R_(f)=0.2) showed complete conversionof starting material. The reaction mixture was diluted withdichloromethane (200 mL) and washed with water (3×200 mL). The organiclayer was then dried over anhydrous magnesium sulfate and concentratedto afford a solid compound, which was purified through columnchromatography (silica gel: 100-200 mesh, eluent: 15% ethyl acetate inhexane) to afford the pure compound (8.8 g, 78.6%). ¹H NMR (CDCl₃, 400MHz): δ 9.57 (s, 1H), 7.32 (t, 1H), 7.12-7.21 (m, 6H), 5.16 (s, 1H),4.10-4.16 (m, 2H), 3.00 (s, 3H), 2.26 (s, 3H), 1.16 (t, 3H).

Step h: Step-g product (4 g, 10.9 mmol), was dissolved in THF (60 mL).Aqueous LiOH solution (1M, 33 mL, 33 mmol) was added dropwise at 0° C.to it. The reaction mixture was then stirred at ambient temperature for16 h. TLC (30% ethyl acetate-Hexane, R_(f)=0.05) showed completeconsumption of starting material. The solvent was removed under reducedpressure and residue was diluted with water (70 mL). The aqueous layerwas washed with ethyl acetate (50 mL) and aqueous part was acidifiedwith 2N HCl up to pH=3-4. The acidified aqueous part was then extractedwith ethyl acetate (3×50 mL). The combine organic part was dried overanhydrous magnesium sulfate and concentrated under reduced pressure toafford a white solid compound (3.1 g, 84%). ¹H NMR (CDCl₃, 400 MHz): δ9.57 (s, 1H), 7.32 (t, 1H), 7.12-7.21 (m, 6H), 5.16 (s, 1H), 3.00 (s,3H), 2.26 (s, 3H).

6.11.7 Synthesis of2-(3-fluoro-4-(methylsulfonamido)phenyl)-3-phenylpropanoic acid(employed for the synthesis of example compound no. 145)

Step a: 2-amino-3-phenylpropanoic acid (10 g, 60.5 mmol) was dissolvedin concentrated HCl (200 mL) and was cooled to −5° C. Sodium nitritesolution (7.9 g, 115 mmol) in water (30 mL) was added dropwise over theperiod of 30 minutes. After complete addition reaction mixture wasstirred at ambient temperature for 2 h. TLC (in 50% ethylacetate-Hexane, R_(f)=0.4) showed complete consumption of startingmaterial. The aqueous part was extracted in ethyl acetate (3×200 mL).The overall organic layer was washed with water (2×200 mL) and finallywith brine (200 mL). The washed organic layer was dried over anhydrousmagnesium sulfate and concentrated under reduced pressure to afford ayellow liquid (12 g, crude).

Step b: Step-a product (12 g, 65 mmol) dissolved in benzene (240 mL).EtOH (120 mL) and sulphuric acid (2 mL) was added to it. The reactionmixture was refluxed for 4 h using Deanstark apparatus. TLC (20% ethylacetate in hexane, R_(f)=0.6) showed complete consumption of startingmaterial. The organic solvent was concentrated under reduced pressureand the residue was diluted with water (200 mL). The aqueous layer wasextracted with 30% ethyl acetate in hexane (3×200 mL). The overallorganic layer was dried over anhydrous magnesium sulfate andconcentrated under reduced pressure to get a yellowish residue, whichwas purified by column chromatography (silica gel: 100-200 mesh; eluent:2% ethyl acetate in hexane) to afford a light yellow liquid compound.(10 g, 87%). ¹H NMR (CDCl₃, 400 MHz): δ 7.23-7.35 (m, 5H), 4.81 (q, 1H),4.11 (q, 2H), 3.10-3.34 (m, 2H), 1.14 (t, 3H).

Step c: To a stirred suspension of potassium tert-butoxide (14.3 g, 127mmol) in dimethylformamide (90 mL), a mixture of step-b product (13.5 g,63.5 mmol) and 1-fluoro 2-nitrobenzene (7.12 g, 63.5 mmol) indimethylformamide (50 mL) was added at −30° C. The reaction mixture wasstirred for 30 minutes at the same temperature. TLC (10% ethylacetate-Hexane, R_(f)=0.4) showed complete consumption of startingmaterial. Reaction mixture was diluted with water (1.5 L) and extractedwith 20% ethyl acetate in hexane (3×250 mL). Then the organic layer wasdried over anhydrous magnesium sulfate. The removal of organic solventunder reduced pressure afforded a yellowish compound, which was purifiedby column chromatography (silica gel: 100-200 mesh, eluent: 2% ethylacetate in hexane) to afford a light brown solid (14.5 g, 72%). ¹H NMR(CDCl₃, 400 MHz): δ 6.64-7.24 (m, 8H), 3.96 (q, 2H), 3.77 (t, 1H), 3.18(q, 1H), 2.90 (q, 1H), 1.02 (t, 3H).

Step d: In a 500 mL round-bottom flask step-c product (14.5 g, 45.7mmol) was dissolved in ethyl acetate (300 mL). Palladium on charcoal(0.700 mg, 10% Pd) was added under nitrogen atmosphere. It was stirredunder atmospheric hydrogen pressure for 12 h. TLC (20% ethyl acetate inhexane, R_(f)=0.4) showed complete conversion of starting material.Reaction mixture was filtered over celite bed and washed with ethylacetate (3×150 mL). The organic layer was concentrated to afford ayellowish residue, which was purified through column chromatography(silica gel: 100-200 mesh, eluent: 10% ethyl acetate in hexane) toafford the pure amine compound (12.5 g, 95%). ¹H NMR (CDCl₃, 400 MHz): δ6.64-7.24 (m, 8H), 5.06 (s, 2H), 3.96 (q, 2H), 3.77 (t, 1H), 3.18 (q,1H), 2.90 (q, 1H), 1.02 (t, 3H).

Step e: Step-d product (12.5 g, 43.5 mmol) was dissolved indichloromethane (190 mL). Pyridine (10.5 mL, 130.5 mmol) was added toit. Methanesulphonylchloride (6 g, 47.85 mmol) was added dropwise to thereaction mixture at 0-5° C. and stirred for 16 h at ambient temperature.TLC (20% ethyl acetate in hexane, R_(f)=0.2) showed complete conversionof starting material. Reaction mixture was diluted with dichloromethane(200 mL) and washed with water (3×200 mL). The organic layer was thendried over anhydrous magnesium sulfate and concentrated to afford asolid compound, which was purified through column chromatography (silicagel: 100-200 mesh, eluent: 20% ethyl acetate in hexane) to afford thepure compound (13.5 g, 85%). ¹H NMR (CDCl₃, 400 MHz): δ 9.57 (s, 1H),7.14-7.34 (m, 8H), 3.94-4.04 (m, 3H), 3.25 (q, 1H), 2.97-3.02 (m, 4H),1.03 (t, 3H).

Step f: Step-e product (4 g, 11 mmol), was dissolved in THF (60 mL).LiOH solution (1M, 33 mL, 33 mmol) was added dropwise at 10-15° C. toit. The reaction mixture was then stirred at ambient temperature for 16h. TLC (in 30% ethyl acetate-Hexane, R_(f)=0.05) showed completeconsumption of starting material. The solvent was removed under reducedpressure and residue was diluted with water (150 mL). The aqueous layerwas washed with ethyl acetate (150 mL) and aqueous part was acidifiedwith 2N aqueous HCl solution up to pH=3-4. The acidified aqueous partwas then extracted with ethyl acetate (3×150 mL). The organic layer wasdried over anhydrous magnesium sulfate and concentrated under reducedpressure afforded a white solid compound (3 g, 81%). ¹H NMR (CDCl₃, 400MHz): δ 12.53 (s, 1H), 9.56 (s, 1H), 7.15-7.33 (m, 8H), 3.91 (t, 1H),3.26 (q, 1H), 3.00 (s, 3H), 2.96 (t, 1H). MS m/z (M+1): 338.

7. Preparation of Selected Amines of General Formula (VI) 7.1 Synthesisof 4-cyclopropyl-3-fluoroaniline hydrochloride (employed for thesynthesis of example compound no. 126)

Step a: To a mixture of 4-bromo 3-fluoro aniline (5 g, 26.4 mmol) inwater (40 mL), was added Boc-anhydride (6.4 g, 29.09 mmol) and stirredat room temperature for 16 h until complete consumption. To the clearsolution water (50 mL) was added to obtain white precipitate, the solidfiltered, washed with water (2×20 mL) and dried under reduced pressureto afford a white solid (5.82 g, 76%).

Step b: A suspension containing step-a product (1 g, 3.46 mmol),cyclopropyl boronic acid (0.74 mmol), tricyclohexyl phosphine (0.387 mg,1.38 mmol), tripotassium phosphate (3.67 g, 17.38 mmol) in toluene (10mL) and water (10 mL) was degassed by purging Ar for 30 minutes andPd(OAc)₂ (155 mg, 0.69 mmol) was added. The mixture was stirred in asealed tube at 110° C. for 20 h. The reaction mixture was cooled to roomtemperature, diluted with ethyl acetate (200 mL), washed with water(2×30 mL), brine solution (25 ml), dried (Na₂SO₄) and concentrated underreduced pressure to give a residue. Purification by columnchromatography (silica gel; 100-200 mesh; eluent: 2% ethylacetate-petroleum ether) afforded a white solid (600 mg, 69%).

Step c: To step-b product (2.65 g, 10.55 mmol), a solution of HCl indiethyl ether (60 ml) was added at 0° C. and the mixture was stirred atroom temperature for 36 h. The solid was filtered, washed with ether(3×10 mL), pentane (3×10 mL) and dried to afford desired compound aswhite solid (810 mg, 43%).

7.2 Synthesis of 4-(cyclopropylethynyl)-3-fluoroaniline (employed forthe synthesis of example compound no. 139)

Step a: To a stirred solution of 4-iodo 3-fluoro aniline (2.25 g, 9.49mmol) in THF (25 ml) at 0° C. to −5° C., CuI (90 mg, 0.47 mmol) and Et₃N(3.5 ml, 25.62 mmol) were added. The reaction mixture was deoxygenatedby purging with a stream of Argon for 30 minutes at −5° C. Addition ofPd(dppf)Cl₂.CH₂Cl₂ (346 mg, 0.47 mmol) and purging was continued. After10 minutes, cyclopropyl acetylene (0.72 ml, 8.54 mmol) was added at −5°C. and stirred at room temperature for 16 h. The reaction mixture wasdiluted with ether (200 mL), filtered through celite pad, washed withether (2×25 mL). The filtrate was concentrated and the residue purifiedby column chromatography (100-200 mesh silica gel) using hexane aseluent to afford title compound as pale brown liquid (750 mg, 45%).

8. Preparation of Selected Carbamate Phenyl Esters of General Formula(VIa) or (V) and Phenyl Esters of General Formula (IVa) 8.1 Synthesis ofmethyl phenyl(3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methylcarbamate(employed for the synthesis of example compounds no. 57-65, 122 and 144)

Step a: To a solution of(3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methanamine (5 g, 18mmol) in dimethylformamide (25 ml, 5 times), potassium carbonate (9.16g, 66 mmol, 3.5 eq) was added and cooled the contents to 0° C. Thenphenyl chloroformate (3.28 g (2.65 ml), 20 mmol, 1.1 eq) was addeddropwise for 15 minutes and the overall reaction mixture was stirred foranother 15 minutes at 0° C. Progress of the reaction was monitored byTLC (20% ethyl acetate-hexane, R_(f)˜0.3). On completion of thereaction, reaction contents were filtered, filtrate was diluted withcold water (100 ml) and the product extracted with ethyl acetate (3×25ml). Combined organic layer was washed with brine solution (100 ml),dried over sodium sulfate and concentrated under reduced pressure. Crudeobtained was purified by column chromatography (silica gel, 10% ethylacetate-hexane) to yield the required product as a white solid (3.2 g,45%).

9. Preparation of Additional Selected Pyrazol Derivatives According toGeneral Formula (II) 9.1 Synthesis of(1-(3-chlorophenyl)-4-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine(employed for the synthesis of example compounds no. 84 and 134)

Step a: To a solution of diispropylamine (40.8 g (57 ml), 0.404 mol, 2.3eq) in THF (400 ml), n-BuLi (1.6 molar) (24.7 g (258.3 ml, 0.38 mol, 2.2eq) was added drop wise for 2 hrs at −20° C. and stirred the contentsfor 30-45 min at 0° C. Cooled the contents to −75° C., a solution ofethyl 2,2,2-trifluoroacetate (25 g, 0.17 mol) in THF (200 ml) was addeddrop wise for 2 hrs. The reaction mixture was stirred initially for 1 hrat −75° C. and later for another 1 hr at rt. Progress of the reactionwas monitored by TLC (50% ethyl acetate/hexane, R_(f)˜0.5). Oncompletion of the reaction, quenched the reaction with ice water (700ml) and the solvents were distilled off completely. Residue washed withDCM (3×300 ml), acidified the contents with 30% HCl solution and theproduct extracted with ether (3×400 ml). Combined organic layer wasdried over sodium sulfate, concentrated under reduced pressure and thecrude obtained was distilled under vacuum to yield the product at 35°C./0.1 mm as a colorless liquid (17 g, 64% yield).

Step b: A step-a product (10 g, 0.066 mol) was taken in ethanolic HCl(300 ml, 30 times) and 3-chlorophenyl hydrazine (9.43 g, 0.066 mol, 1eq) was added. The reaction mixture was heated to reflux for 2 hrs.Progress of the reaction was monitored by TLC (20% ethyl acetate/hexane,R_(f)˜0.3). On completion of the reaction, reaction contents wereconcentrated and the residue taken in water (200 ml). Basified thecontents to a pH˜12 with 1N NaOH solution and filtered the contents.Solid obtained was taken in ethyl acetate (200 ml), dried the contentsover sodium sulfate and concentrated under reduced pressure to yield therequired product as a red colored solid (12 g, 65% yield).

Step c: Cupric bromide (11.33 g, 0.0511 mol, 1.2 eq) was taken inacetonitrile (176 ml) and heated to 150° C. Then n-butyl nitrite (6.59 g(7.47 ml), 0.063 mol, 1.5 eq) was added followed by a solution of step-bproduct (11.75 g, 0.042 mol) in acetonitrile (176 ml) was added dropwise for 30 min at 150° C. and stirred for 15 min. Progress of thereaction was monitored by TLC (5% ethyl acetate/hexane, Rf˜0.7). Oncompletion of the reaction, acetonitrile was distilled off, residue wastaken in ice cold water (300 ml) and the product extracted with ethylacetate (5×100 ml). Combined extract was dried over sodium sulfate,concentrated under reduced pressure and the crude obtained was subjectedto column chromatography (silica gel, pure hexane). Pure product was notisolated and a mixture was obtained as a red colored liquid (16 g,crude) and the same product used for the next step.

Step d: To a solution of step-c product (13 g, 0.038 mol) in NMP (130ml, 10 times), copper cyanide (6.8 g, 0.076 mol, 2 eq), sodium iodide(100 mg, catalytic) were added. The reaction mixture was placed in apre-heated oil bath at 180° C. and allowed to stir for 8 hr. Progress ofthe reaction was monitored by TLC (5% ethyl acetate/hexane, R_(f)˜0.4).On completion of the reaction, diluted the reaction contents with water(200 ml) and the product extracted with ethyl acetate (5×100 ml).Combined extract was washed with cold water (5×50 ml), dried over sodiumsulfate and concentrated under reduced pressure. The crude obtained waspurified by column chromatography (silica gel, 2% ethyl acetate/hexane)to yield the required product as a pale yellow colored solid (8 g).

Step e: To a solution of step-d product (5 g, 0.017 mol) in dry THF (30ml, 6 times), Boran-THF in THF (70 ml) was added drop wise for 30 min at0-5° C. Reaction mixture was slowly heated to 50° C. and allowed to stirfor 12 hrs. Progress of the reaction was monitored by TLC (75% ethylacetate/hexane, Rf˜0.2). On completion of the reaction, acidified thecontents to 0-5° C. with conc. HCl at 0° C. and stirred the contents for2 hrs at rt. Then basified the contents to a pH˜12 with 10% NaOHsolution and the product extracted with ethyl acetate (5×50 ml).Combined extract was dried over sodium sulfate and concentrated underreduced pressure. Solid obtained was washed with 10% ether/hexane anddried to yield the required product as a white colored solid (3 g, 59%yield, mp 82-86° C.).

9.2 Synthesis of(1-(3-chlorophenyl)-3-cyclopropyl-1H-pyrazol-5-yl)methanaminehydrochloride (employed for the synthesis of example compound no. 128)

Step a: To a solution of sodium ethoxide (freshly prepared by dissolvingsodium (1 g, 8.2 mmol, 1.2 eq) in EtOH (30 mL)), diethyl oxalate (0.92mL, 6.85 mmol, 1 eq) was added at room temperature followed by additionof cyclopropyl methyl ketone (0.74 mL, 7.5 mmol, 1.1 eq) dropwise at 0°C. The reaction mixture was slowly warmed to room temperature andstirred for 3 h. Ice cold water (10 mL) was added and EtOH wasevaporated under reduced pressure. The residual aqueous layer wasdiluted with 2 N aq. HCl (15 mL) and extracted with diethyl ether (2×25mL). The organic layer was washed with brine solution and dried(Na₂SO₄), filtered and concentrated to give a pale brown liquid (400 mg,31%).

Step b: To a solution of step-a product (200 mg, 0.543 mmol, 1 eq) inEtOH (8 mL), methoxylamine hydrochloride (30% solution in water, 0.4 mL,0.651 mmol, 1.2 eq) was added at room temperature and the reactionmixture stirred for 1 h. EtOH was evaporated under reduced pressure andthe residual aqueous layer was extracted with ethyl acetate (15 mL). Theorganic layer was washed with water (10 mL), brine solution (10 ml),dried (Na₂SO₄), filtered and concentrated under reduced pressure to givea pale yellow liquid (180 mg, 78%).

Step c: A mixture of step-b product (1.1 g, 5.164 mmol, 1 eq) and3-chlorophenyl hydrazine hydrochloride (1.84 g, 10.27 mmol, 2 eq) wastaken in acetic acid (20 mL), 2-methoxy EtOH (10 mL) and the reactionmixture was heated at 105° C. for 3 h. Solvent was evaporated and theresidue was extracted with ethyl acetate (60 mL). The organic layerwashed with water (10 mL), brine solution (10 ml), dried (Na₂SO₄),filtered and concentrated under reduced pressure to give a residue.Purification by column chromatography (silica gel: 100-200 mesh; eluent:ethyl acetate-petroleum ether (4:96)) afforded a pale brown semi solid(1.15 g, 77%).

Step d: To a solution of step-c product (2.5 g, 8.62 mmol, 1 eq) in THF(15 mL)—MeOH (9 mL)—water (3 mL), LiOH (1.08 g, 25.71 mmol, 3 eq) wasadded at 0° C. and the reaction mixture was stirred for 2 h at roomtemperature. Solvent was evaporated and pH of the residue was adjustedto −3 sing 2 N aqueous HCl (1.2 mL). The acidic aqueous layer wasextracted with ethyl acetate (2×60 mL); the combined organic layerwashed with water (10 mL), brine solution (10 ml), dried (Na₂SO₄),filtered and concentrated under reduced pressure to give an off whitesolid (1.4 g, 62%).

Step e: To a solution of step-d product (1.4 g, 5.34 mmol, 1 eq) in1,4-dioxane (30 mL), pyridine (0.25 mL, 3.2 mmol, 0.6 eq) and (Boc)₂O(1.4 mL, 6.37 mmol, 1.2 eq) were added at 0° C. and the resultingmixture was stirred for 30 minutes at the same temperature. Ammoniumbicarbonate (0.84 g, 10.63 mmol, 2 eq) was added at 0° C. and thereaction mixture was stirred at room temperature overnight. The reactionmixture was diluted with water (10 mL) and the aqueous layer wasextracted with ethyl acetate (2×30 mL). The organic layer was washedwith 2N HCl (20 mL), water (10 mL), brine solution (10 ml), dried(Na₂SO₄), filtered and concentrated under reduced pressure to give aresidue. Purification by column chromatography (silica gel: 100-200mesh; eluent: ethyl acetate-petroleum ether (16:84)) gave a white solid(1 g, 72%).

Step f: To a solution of step-e product (2 g, 7.66 mmol, 1 eq) in THF(25 mL), BH₃.DMS (1.44 mL, 15.32 mmol, 2 eq) was added at 0° C. and thereaction mixture was heated at 70° C. for 3 h. The reaction mixture wascooled to 0° C. and MeOH (15 mL) was added and reaction mixture heatedat reflux for 1 h. The reaction mixture was brought to room temperatureand solvent was evaporated under reduced pressure. The residue wasdissolved in ether (15 mL), cooled to 0° C. and a solution of HCl in1,4-dioxane (3 mL) was added (pH of the reaction mixture ˜4). Theprecipitated solid was filtered and washed with diethyl ether (5 mL,thrice) to give the hydrochloride salt compound as a white solid (600mg, 28%).

9.3 Synthesis of(3-tert-butyl-1-(pyridin-2-yl)-1H-pyrazol-5-yl)methanamine (employed forthe synthesis of example compound no. 127)

Step a: To a solution of 2-chloropyridine (20 g, 0.17 mol) in ethanol(100 ml, 5 times), hydrazine hydrate (132 ml, 6.6 times) was added andthe reaction mixture was heated to reflux for 15 hrs. Progress of thereaction was monitored by TLC (40% ethyl acetate/hexane, Rf˜0.1). As thereaction not completed, continued to reflux for another 15 hrs andmonitored by TLC. On completion of the reaction, ethanolic hydrazinehydrochloride was distilled off completely at 100° C., residue was takenin DCM (500 ml) and washed the contents with saturated sodium carbonatesolution (100 ml). Combined organic layer was dried over sodium sulfateand concentrated under reduced pressure to obtain the crude product as alow melting solid (11 g, crude). The crude obtained was directly usedfor the next step.

Step b: To a stirred solution of step-a product (11 g, crude) in ethanol(110 ml, 10 times), 4,4-dimethyl-3-oxopentanenitrile (11.3 g, 0.09 mol,0.9 eq) was added portion wise followed by catalytic amount of HCl. Thereaction mixture was heated to 100° C. and refluxed for 6 hrs. Progressof the reaction was monitored by TLC (20% ethyl acetate/hexane, Rf˜0.7).On completion of the reaction, ethanol was distilled off, residue wastaken in water (200 ml) and the product extracted with ethyl acetate(2×100 ml). Combined extract was dried over sodium sulfate, concentratedunder reduced pressure and the crude obtained was purified by columnchromatography (silica gel, 10% ethyl acetate/hexane) to yield therequired product as an off white solid (18 g).

Step c: To a solution of step-b product (4 g, 0.01 mol) in acetonitrile(80 ml), cupric chloride (12.3 g, 0.09 mol, 5 eq) was added. A solutionof tert-butyl nitrite (2.8 (3.3 ml), 0.023 mol, 1.5 eq) in acetonitrile(40 ml (total 120 ml, 30 times)) was added drop wise for 10 min and theoverall reaction mass was stirred for 5 hrs at rt. Progress of thereaction was monitored by TLC (10% ethyl acetate/hexane, Rf˜0.3). Oncompletion of the reaction, acetonitrile was distilled off, residue wastaken in water (100 ml) and the product extracted with ethyl acetate(2×200 ml). Combined extract was dried over sodium sulfate, concentratedunder reduced pressure and the crude was purified by columnchromatography (silica gel, 4% ethyl acetate/hexane) to yield therequired product as a pale yellow colored liquid (2.1 g, 48% yield).

Step d: To a stirred solution of step-c product (2.1 g, 0.008 mol) inNMP (21 ml, 1 time), copper cyanide (1.56 g, 0.017 mol, 2 eq) was addedportion wise followed by a catalytic amount of sodium iodide was added.The reaction mixture was heated to 180° C. and maintained at thattemperature for 4 hrs. Progress of the reaction was monitored by TLC(10% ethyl acetate/hexane, Rf˜0.5). On completion of the reaction,diluted the reaction contents with ethyl acetate, filtered the contentsthrough celite bed and the filtrate washed with cold water (50 ml).Organic layer was dried over sodium sulfate, concentrated under reducedpressure and the crude was purified by column chromatography (silicagel, 6-8% ethyl acetate/hexane) to yield the required product as an offwhite solid (0.8 g, 40% yield).

Step e: To a solution of step-d product (1.5 g, 0.006 mol) in methanol(20 ml), catalytic amount of raney nickel. The reaction mixture washydrogenated for 1 hr at 60 psi. Progress of the reaction was monitoredby TLC (15% ethyl acetate/hexane, Rf˜0.1). On disappearance of thestarting material, filtered the contents on celite bed and washed withmethanol. To the filtrate was purified by column chromatography (silicagel, 6% ethyl acetate/hexane) to yield the titled product as a creamcolored oil (1.4 g, 97% yield).

9.4 Synthesis of(1-(pyridin-3-yl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanaminehydrochloride (employed for the synthesis of example compound no. 136)

Step a: To a cold solution of pyridin-3-amine (40 g, 425.5 mmol) inconc. HCl (500 mL) at 0° C., a solution of NaNO₂ (35.23 g, 510.6 mmol)in water (40 mL) was added dropwise maintaining the temperature at 0° C.for 15 minutes. After addition the solution was stirred for 20 minutes.This solution was added to a solution of SnCl₂ (177.5 g, 936.3 mmol) inconc. HCl (100 mL) dropwise maintaining the temperature at 0° C. for 20minutes and the resulting yellow solution was stirred at 0° C. for 30minutes. The obtained yellow solid was filtered, washed with water (3×50mL) and dried afford product (106.5 g, crude) as yellow solid.

Step b: To a cold suspension of NaH (60% dispersion in oil, 29.26 g,731.7 mmol) in 1,4-dioxane (450 mL), acetonitrile (38.46 mL, 731.7 mmol)was added dropwise at 0° C. and stirred for 30 minutes. The reactionmixture was cooled to −5° C., ethyl 2,2,2-trifluoroacetate (83.12 g,585.36 mmol) was slowly added and the reaction mixture allowed to stirat room temperature for 16 h. The reaction mixture was cooled to 0° C.,quenched with MeOH (150 mL), diluted with ethyl acetate (300 mL) and pHadjusted to −4 using dilute aqueous HCl. The organic layer was separatedand the aqueous layer was extracted with ethyl acetate (2×250 mL). Thecombined ethyl acetate layer was washed with water (250 mL), brinesolution (200 mL), dried (Na₂SO₄), filtered and concentrated underreduced pressure to afford a brown liquid (57 g). The crude compound wasused as such without further purification.

Step c: A solution of step-b product (57 g, crude; 416.05 mmol) andstep-a product (60.5 g, 416.05 mmol) in EtOH (650 mL) was stirred atreflux for 3 h. The reaction mixture was concentrated; the obtainedresidue was diluted with ethyl acetate (2 L), washed with water (2×500mL), brine solution (500 mL), dried (Na₂SO₄), filtered and concentratedunder reduced pressure to give a residue. Purification by columnchromatography (silica gel; 100-200 mesh; eluent: 30% ethyl acetate inpetroleum ether) afforded a yellow solid (31.48 g).

Step d: To a cold suspension of potassium iodide (51.3 g, 309.21 mmol)and isoamyl nitrite (41.16 mL, 309.21 mmol) in dry acetonitrile (350mL), a solution of step-c product (23.5 g, 103.07 mmol) in acetonitrile(100 mL) was added dropwise at 0° C. and the reaction mixture wasstirred at 100° C. for 20 h. The reaction mixture was concentrated; theobtained residue was diluted with ethyl acetate (1 L), washed with water(2×400 mL), brine solution (200 mL), dried (Na₂SO₄), filtered andconcentrated to give a residue. Purification by column chromatography(silica gel; 100-200 mesh; eluent: 30% ethyl acetate in petroleum ether)afforded a pale yellow solid (16.52 g, 37%).

Step e: To a solution of step-d product (16.5 g, 48.67 mmol) in dry NMP(150 mL), CuCN (6.53 g, 73.0 mmol) was added and the reaction mixturewas stirred at 200° C. for 2 h. The reaction mixture was cooled to roomtemperature, quenched with ethylene diamine (50 mL) and diluted withethyl acetate (800 mL). The obtained suspension was filtered throughcelite bed, washed with ethyl acetate (2×100 mL). The combine filtratewas washed with water (2×300 mL), brine solution (250 mL), dried(Na₂SO₄), filtered and concentrated under reduced pressure to give aresidue. Purification by column chromatography (silica gel; 100-200mesh; eluent: 20-30% ethyl acetate in petroleum ether) to afford ayellow solid (5.12 g, 44%).

Step f: To a solution of step-e product (4.5 g, 18.9 mmol) in saturatedmethanolic NH₃ (50 mL), Raney-Nickel (3 g, wet, washed with MeOH (4×5mL)) was added and the mixture was hydrogenated in a Parr hydrogenatorat 40 Psi pressure at room temperature for 4 h. The reaction mixture wasfiltered through celite and the filtrate was concentrated under reducedpressure. The obtained residue was stirred in sat. HCl in ether (50 mL)for 2 h. Ether was decanted, the obtained solid was washed with ether(3×10 mL), vacuum dried to afford product compound as light brown solid(1.2 g, 23%).

9.5 Synthesis of5-(aminomethyl)-3-tert-butyl-N-(2,2,2-trifluoroethyl)-1H-pyrazol-1-amine(employed for the synthesis of example compound no. 98)

Step a: To a solution of tert-butyl-1H-pyrazole-5-carbonitrile (5 g,0.033 mol) in methanol (100 ml, 20 times), Raney nickel (5 g, 1 times)was added and the reaction mixture was hydrogenated for 1-2 hrs 70 psi.Progress of the reaction was monitored by TLC (40% ethyl acetate/hexane,R_(f)˜0.1). On completion of the reaction, filtered the reactioncontents and the bed was washed with methanol (100 ml). Methanol wasdistilled off completely and the crude obtained as a pale yellow coloredliquid (5 g., crude) was directly used for the next step.

Step b: To a stirred solution of step-a product (5 g, crude) in methanol(50 ml, 10 times), sodium carbonate (5.1 g, 0.04 mol, 1.5 eq) was addedand stirred for 15 min. Cooled the contents to 0° C., Boc anhydride(6.97 g, 1.1 eq) was added drop wise for 10 min and the overall reactionmixture was stirred for 30 min at 0° C. Progress of the reaction wasmonitored by TLC (50% ethyl acetate/hexane, Rf˜0.3). On completion ofthe reaction, methanol was distilled off completely, residue was takenin water (100 ml) and the product extracted with ethyl acetate (2×100ml). Combined extract was dried over sodium sulfate, concentrated underreduced pressure and the crude was recrystalised from hexane to yieldthe required product as a white solid (4.5 g).

Step c: To a stirred solution of step-b product (5 g, 0.019 mol) in DMF(50 ml, 10 times), sodium hydroxide (7.9 g, 0.19 mol, 10 eq) was added.Cooled the contents to 0° C., Hydroxylamine-o-sulfonic acid (6.4 g,0.057 mol, 3 eq) was added portion wise for 30 min and the reactionmixture was stirred for 2 hrs at 0° C. Progress of the reaction wasmonitored by TLC (30% ethyl acetate/hexane, Rf˜0.4). On completion ofthe reaction, poured the reaction contents into crushed ice (200 g) andfiltered the contents. Solid obtained was taken in hexane (100 ml),filtered and dried to yield the required product as a white solid (4 g,75% yield).

Step d: To a stirred solution of step-c product (2 g, 0.001 mol) inethanol (20 ml, 10 times), ether containing trifluoroacetaldehyde (1.41g in 50 ml (0.014 mol, 2 eq)) was added. The reaction mixture wasstirred for 12 hrs at rt. Progress of the reaction was monitored by TLC(10% ethyl acetate/hexane, R_(f)˜0.7). On completion of the reaction,ethanol was distilled off completely and the crude obtained was purifiedby column chromatography (silica gel, hexane) to yield the requiredproduct as a white solid (2 g, 77% yield).

Step e: To a stirred solution of step-d product (1.7 g, 0.0048 mol) inmethanol (170 ml), 10% Pd/C (0.5 g, catalytic) was added. The reactionmixture was stirred for 12 hrs under Hydrogen balloon pressure. Progressof the reaction was monitored by TLC (10% ethyl acetate/hexane,R_(f)˜0.3). On completion of the reaction, filtered the contents overcelite bed and the bed washed with methanol. Methanol distilled off fromthe filtrate and the crude obtained was purified by columnchromatography (basic alumina, hexane) to yield the titled product as awhite solid (1.02 g, 50% yield, mp 80-83° C.).

Step f: To a stirred solution of Boc-compound step e product (1.0 g),DCM (20 ml) was added at RT and stirred for about 20 min. This reactionmixture was cooled to 0-5° C. and pass the HCl gas for about 30 min.Progress of the reaction was monitored by TLC (10% ethylacetate/hexane/50% ethyl acetate/hexane). On completion of the reaction,distill off DCM. Add water (20 ml) then extract the compound with 20%IPA/CHCl₃ and the layer were separated. The organic layer was distilledoff under reduced pressure and dried under high vacuum. The crude wasobtained by washing with heptane and drying under high vacuum. Thecompound was obtained light yellow colored viscous liquid (0.65 g, 91%yield).

9.6 Synthesis of(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine(employed for the synthesis of example compound no. 132)

Step a: DMAP (4.25 g, 0.034 mol, 0.01 eq) was added to DCM (3 ltrs) andcooled the contents to −10° C. Trifluoroacetic anhydride (765 g (510ml), 3.2 mol, 1.05 eq) was added followed by ethyl vinyl ether (250 g,3.04 mol) was added drop wise for 45 min at −10° C. Then the overallreaction mixture was initially stirred for 8 hrs at 0° C. and later forovernight at RT. Progress of the reaction was monitored by TLC (10%ethyl acetate/hexane, Rf˜0.7). On completion of the reaction, reactioncontents were quenched with saturated NaHCO₃ solution (600 ml) andorganic layer was separated. Aqueous layer was extracted with DCM (2×500ml). Combined organic layer was washed with water (2×1 ltr), dried oversodium sulfate and concentrated under reduced pressure to obtain thecrude product as a brown colored liquid (450 g, crude).

Step b: Hydrazine dihydrochloride (225 g, 2.14 mol, 1.6 eq) was taken inethanol (1400 ml) and stirred well. TEA (135.4 g (185.4 ml), 1.34 mol, 1eq) was added drop wise for 45 min at RT. Then step-a product (225 g,crude) was added drop wise at RT and the overall reaction mixture wasrefluxed for overnight. Progress of the reaction was monitored by TLC(20% ethyl acetate/hexane, R_(f)˜0.4). On completion of the reaction,ethanol was distilled off completely, residue was taken in ice water(500 ml) and the product extracted with ethyl acetate (2×400 ml).Combined extract was washed with ice water (300 ml), dried over sodiumsulfate and concentrated under reduced pressure to yield the requiredproduct as and off white solid (195 g).

Step c: NaH (33.08 g (19.85, 60%), 1.5 eq) was added to small quantityof hexane and stirred well for 10 min. Hexane was decanted, dry DMF (500ml) was added drop wise under N₂ atmosphere and stirred well. A solutionof step-b product (75 g, 0.55 mol) in DMF (125 ml) was added drop wiseunder N₂ atmosphere. Then a solution of 4-methoxylbenzoyl chloride (86.3g, 0.55 mol, 1 eq) in DMF (125 ml) was added drop wise and the overallreaction mixture was allowed to stir for 12 hrs at RT. Progress of thereaction was monitored by TLC (10% ethyl acetate/hexane, Rf˜0.4). Oncompletion of the reaction, reaction contents were poured into ice water(500 ml) and the product extracted with ethyl acetate (2×400 ml). Thenthe contents were dried over sodium sulfate and concentrated underreduced pressure to yield the required product as a brown colored liquid(125 g, 88% yield).

Step d: Diisopropyl amine (28.4 (39.4 ml), 1.2 eq) was taken in THF (500ml), stirred well and cooled the contents to 0° C. n-BuLi (234.4 ml, 1.5eq) was added drop wise at 0° C. and cooled the contents to −78° C. Asolution of step-c product (62 g, 0.24 mol) in THF (200 ml) was addeddrop wise for 30 min and stirred the contents for another 30 min at −78°C. Then dry CO₂ gas was bubbled through the reaction mixture for 1.5 hrsand the progress of the reaction was monitored by TLC (10% ethylacetate/hexane, R_(f)˜0.1). On completion of the reaction, reactioncontents were poured into ice water (300 ml) and the aqueous layer wasextracted with ethyl acetate (2×200 ml) in basic condition. Aqueouslayer was acidified with 20% HCl solution and extracted with ethylacetate (2×200 ml). Combined organic layer was dried over sodium sulfateand concentrated under reduced pressure to yield the required product asan off white solid (42 g, 58% yield).

Step e: To a solution of step-d product (50 g, 0.16 mol) in DCM (750 ml,15 times), catalytic amount of DMF was added and cooled to 0° C. Thionylchloride (99.3 g (61 ml), 0.83 mol, 5 eq) was added drop wise for 30 minat 0° C. Overall reaction mixture was slowly heated to a refluxtemperature and allowed to reflux for 2 hrs. Progress of the reactionwas monitored by TLC (10% ethyl acetate/hexane, R_(f)˜0.4). Ondisappearance of the starting material, DCM was distilled offcompletely. Above prepared acid chloride was dissolved in DCM (500 ml)and added drop wise to aqueous ammonia solution (600-700 ml) at 0° C.Overall reaction mixture was allowed to stir for 1 hr and the progressof the reaction was monitored by TLC (10% ethyl acetate/hexane, Rf˜0.7).On completion of the reaction, ice cold water (200 ml) was added and theproduct extracted with ethyl acetate (2×200 ml). Combined organic layerwas dried over sodium sulfate and concentrated under reduced pressure toyield the required product as an off white solid (37 g, crude). Crudeobtained was directly used for the next step.

Step f: LAH (4.7 g, 0.12 mol, 1 eq) was added to small quantity ofhexane and stirred well for 10 min. Hexane was decanted and THF (250 ml)was added to LAH under cold condition. Then a solution of step-e product(37 g, 0.12 mol) in THF (120 ml) was added drop wise for 30 min at 0° C.and reaction mixture was heated to reflux for 5 hrs. Progress of thereaction was monitored by TLC (50% ethyl acetate/hexane, R_(f)˜0.2). Asthe reaction moved completely, LAH (2.3 g) was added and refluxed foranother 4 hrs. This time reaction was moved completely. Then thereaction contents were slowly added to saturated solution of sodiumsulfate (1 ltr) and the product extracted with ethyl acetate (2×500 ml).Combined extract was dried over sodium sulfate and concentrated underreduced pressure to obtain the crude product as an off white solid (32.5g). Crude obtained was directly used for the next step.

Step g: To a solution of step-f product ((80 g, 0.28 mol) in DCM (600ml) cooled at 0° C., TEA (22.7 g (30.2 ml), 0.026 mol, 0.8 eq) was addeddrop wise for 10 min. Then Boc anhydride (61.2 g (62.5 ml), 0.28 mol, 1eq) taken in DCM (200 ml) was added drop wise for 20-30 min at 0° C.Overall reaction mixture initially stirred for 30 min at 0° C. and alterfor another 30 min at RT. Progress of the reaction was monitored by theTLC (20% ethyl acetate/hexane, R_(f)˜0.6). On completion of thereaction, DCM was distilled off completely, residue was taken in icewater (500 ml) and the product extracted with ethyl acetate (2×300 ml).Combined extract was dried over sodium sulfate and concentrated underreduced pressure. Crude obtained was recrystalised from hexane (200 ml)to yield the required product as an off white solid (80 g, 74% yield).

Step h: Step-g (5 g, 0.012 mol) product was taken in DCM (30 ml, 6times) and cooled to 0° C. HCl gas was bubbled through the reactionmixture for 45 min at 0° C. Progress of the reaction was monitored byTLC (30% ethyl acetate/hexane, R_(f)˜0.2). On completion of thereaction, DCM was distilled off completely. Residue was taken in icewater (200 ml) and the product extracted with 20% ethyl acetate/hexane(2×100 ml). Aqueous layer was basified to a pH˜10 with 2N NaOH solutionand extracted with ethyl acetate (5×100 ml). Combined organic layer waswashed with water (2×200 ml), dried over sodium sulfate and concentratedunder reduced pressure to yield the required product as an yellowcolored liquid (2.4 g, 64% yield).

9.7 Synthesis ofN-(5-(aminomethyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzamide(employed for the synthesis of example compound no. 146)

Step a: To a stirred solution of tert-butyl(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylcarbamate(20 g, 0.052 mol) in toluene (300 ml, 15 times) cooled at 0° C.,aluminum chloride (17.34 g, 0.129 mol, 2.5 eq) was added portion wisefor 30 min. Reaction mixture was slowly heated to 50-60° C. and allowedstir for 2 hrs at the same temperature. Progress of the reaction wasmonitored by TLC (20% ethyl acetate/hexane, R_(f)˜0.1). On completion ofthe reaction, reaction contents were quenched with dilute HCl, ice coldwater (300 ml) was added and extracted with ethyl acetate (2×100 ml).Aqueous layer was basified with sodium hydroxide solution and extractedwith ethyl acetate. Combined extract was dried over sodium sulfate andconcentrated under reduced pressure to obtain the crude product as abrown colored solid (4.6 g). The crude obtained was directly used forthe next step.

Step b: To a stirred solution of step-a product (5.7 g, 0.034 mol) inDCM (37 ml) cooled at 0° C., TEA (1.74 g (2.4 ml), 0.017 mol, 0.5 eq)was added drop wise for 10 min. Then Boc anhydride (3.76 g (3.9 ml),0.017 mol, 0.5 eq) taken in DCM (20 ml) was added drop wise for 10-15min at 0° C. Overall reaction mixture initially stirred for 30 min at 0°C. and alter for another 30 min at RT. Progress of the reaction wasmonitored by the TLC (20% ethyl acetate/hexane, R_(f)˜0.6). As thereaction not moved completely, Boc anhydride (0.3 eq) was added andstirred for another 15 min at RT. Progress of the reaction was monitoredby TLC and found that the reaction moved completely. DCM was distilledoff completely, residue was taken in ice water (300 ml) and the productextracted with ethyl acetate (2×200 ml). Combined extract was dried oversodium sulfate and concentrated under reduced pressure to yield therequired product as and off white solid (7 g, 76% yield).

Step c: A solution of step-b product (10 g, 0.037 mol) in DMF (50 ml)was added drop wise to a mixture of NaH (1.85 g, 0.077 mol, 1.2 eq) inDMF (50 ml) for 45 min at RT. Then 0.5M monochloro amine solution (322ml) was added drop wise for 30 min and the overall reaction mixture wasallowed to stir for 20 min at RT. Progress of the reaction was monitoredby TLC (30% ethyl acetate/hexane, R_(f)˜0.5). On completion of thereaction, reaction contents were quenched with saturate Na₂S₂O₃ solutionin cold condition and the product was extracted with ethyl acetate(5×100 ml). Combined extract was dried over sodium sulfate, concentratedunder reduced pressure and the crude obtained was purified by columnchromatography (silica gel, 4% ethyl acetate/hexane) to yield therequired product as an off white solid (4 g, 62% yield).

Step d: To a solution of step-c product (1.2 g, 0.0042 mol) in toluene(12 ml, 10 times), potassium carbonate (1.18 g, 2 eq), water (12 ml, 10times) and TBAB (0.137 g, 0.0004 mol, 0.1 eq) were added. Then thecontents were stirred for 15 min and cooled to 0° C. Benzoyl chloride(0.72 g, 0.005 mol, 1.2 eq) taken in toluene (6 ml) was added drop wiseat 0° C. and the overall reaction mixture was stirred for 2 hrs at RT.Progress of the reaction was monitored by TLC (30% ethyl acetate/hexane,R_(f)˜0.6). On completion of the reaction, ice water (100 ml) was added,organic layer separated and the aqueous layer extracted with ethylacetate (5×75 ml). Combined organic layer was washed with water (2×100ml) and dried over sodium sulfate. Then the contents were concentratedunder reduced pressure and the crude obtained was purified by columnchromatography (silica gel, 3% ethyl acetate/hexane) to yield therequired product as a pale yellow colored liquid (1.1 g, 67% yield).

Step e: To a solution of step-d product (1.1 g, 0.0028 mol) in DCM (11ml, 10 times) cooled to at 0° C., trifluoroacetic acid (2.2 ml, 2 times)was added drop wise. Overall reaction mixture was allowed to stir for1-1.5 hrs at RT. Progress of the reaction was monitored by TLC (10%ethyl acetate/hexane, Rf˜0.2). On completion of the reaction, DCM wasdistilled off completely. Residue was taken in cold water (200 ml),basified with saturated NaHCO₃ solution and the product extracted withethyl acetate (4×50 ml). Combined extract was washed with water (2×50ml), dried over sodium sulfate and concentrated under reduced pressure.Crude obtained was purified by column chromatography (silica gel, 10%ethyl acetate/hexane) to yield the required product as a white solid(0.24 g, 30% yield).

9.8 Synthesis of5-(aminomethyl)-N-(pyridin-2-ylmethyl)-3-(trifluoromethyl)-1H-pyrazol-1-amine(employed for the synthesis of example compound no. 129)

Step a: To a solution of tert-butyl(1-amino-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylcarbamate (2 g,0.0071 mol) in methanol (15 ml), picolinaldehyde (1.14 g (1 ml), 0.016mol, 1.5 eq) taken in methanol (5 ml) was added. Then the reactionmixture was acidified with acetic acid (0.2 ml, catalytic) and heated toreflux for 24 hrs. Progress of the reaction was monitored by TLC (10%ethyl acetate/hexane, R_(f)˜0.4). On completion of the reaction,methanol was distilled off completely. Residue was taken in ice water(200 ml) and the product extracted with ethyl acetate (4×50 ml).Combined extract was washed with water (2×50 ml), dried over sodiumsulfate and the ethyl acetate was distilled off completely. Crudeobtained was recrystalised from hexane (10 ml) to yield the requiredproduct as liquid (2 g, 76% yield).

Step b: To a solution of step-a product (2 g, 0.0054 mol) in methanol(20 ml, 10 times) cooled to at 0° C., NaBH₄ (0.2 g, 0.0054 mol, 1 eq)was added slowly. Overall reaction mixture was allowed to stir for 1 hrat RT. Progress of the reaction was monitored by TLC (20% ethylacetate/hexane, Rf˜0.2). On completion of the reaction, methanol wasdistilled off completely. Residue was taken in cold water (100 ml) andthe product extracted with ethyl acetate (5×50 ml). Combined extract waswashed with water (2×50 ml), dried over sodium sulfate and concentratedunder reduced pressure. Crude obtained was purified by columnchromatography (silica gel, 10% ethyl acetate/hexane) to yield therequired product pale yellow colored solid (1.1 g, 57% yield).

Step c: To a solution of the Boc compound step b product (1.1 g) in DCM(11 ml, 10 times) cooled to at 0° C., trifluoroacetic acid (2.2 ml, 2times) was added drop wise. Overall reaction mixture was allowed to stirfor 1-1.5 hrs at RT. Progress of the reaction was monitored by TLC (10%ethyl acetate/hexane, R_(f)˜0.2). On completion of the reaction, DCM wasdistilled off completely. Residue was taken in cold water (200 ml),basified with saturated NaHCO₃ solution and the product extracted withethyl acetate (4×50 ml). Combined extract was washed with water (2×50ml), dried over sodium sulfate and concentrated under reduced pressure.Crude obtained was purified by column chromatography (silica gel, 10%ethyl acetate/hexane) to yield the required product as a white solid(0.425 g, 53% yield).

9.9 Synthesis(3-tert-butyl-1-(phenylsulfonyl)-1H-pyrazol-5-yl)methanamine (employedfor the synthesis of example compound no. 108)

Step a: To a stirred solution of 3-tert-butyl-1H-pyrazole-5-carbonitrile(3 g, 20 mmol) in dichloromethane (30 ml, 10 times) TEA (2.44 g (3.36ml), 24 mmol, 1.2 eq) was added at 00° C. Then phenylsulfonyl chloride(2.84 g (2 ml), 10 mmol, 0.8 eq) was added at 00° C. and the reactionmass was stirred for 12 h at room temperature. Progress of the reactionwas monitored by TLC (20% ethyl acetate-hexane, Rf˜0.6). On completionof the reaction, ice water (20 ml) was added to reaction mixture,organic layer was separated and washed with 1N HCl (2×20 ml followed bywith water (2×15 ml), Dried the contents over sodium sulfate,concentrated under reduced pressure and the crude obtained wasrecrystallised from hexane to yield the required product as an off whitesolid (4 g, 68%).

Step b: To a solution of step-a product (2.3 g, 7 mmol) in THF (23 ml,10 times) Boran-DMS (1.81 g (23.8 ml, 20 mmol, 3 eq) was added dropwiseat 0-5° C. Then the reaction mixture was heated to 80° C. and stirredfor 5 h. Progress of the reaction mixture was monitored by TLC (75%ethyl acetate-hexane, R_(f)˜0.6). On completion of the reaction,quenched the reaction mixture with dilute HCl below 5° C. and stirredthe contents for 12 h. Again TLC was monitored (75% ethylacetate-hexane, R_(f)˜0.4). Then the reaction contents were poured inice water (100 ml) and the compound extracted with ethyl acetate (4×40ml). Aqueous layer was basified with 2N NaOH solution at 0-5° C. and thecompound extracted with ethyl acetate (5×20 ml). The combined extractwas washed with water (2×50 ml), dried over sodium sulfate andconcentrated under reduced pressure to obtain the crude product as paleyellow colored liquid (750 mg).

Synthesis of the Exemplary Compounds 1. Preparation of Amides(A=CR^(5b))

General directions for reacting amines of general formula (II) withcarboxylic acids of general formula (III) or carboxylic acid derivativesof general formula (IV) to form compounds of general formula (I),wherein A=CR^(5b) (amides), as in scheme 1a (step j09).

1.1 Method A:

The acid of general formula (III) (1 equivalent), the amine of generalformula (II) (1.2 equivalents) and EDCI (1.2 equivalents) are stirred inDMF (10 mmol of acid/20 ml) for 12 hours at RT and water is subsequentlyadded thereto. The reaction mixture is repeatedly extracted with EE, theaqueous phase is saturated with NaCl and subsequently reextracted withEE. The combined organic phases are washed with 1 N HCl and brine, driedover magnesium sulphate and the solvent is removed under vacuum. Theresidue is purified by means of flash chromatography (SiO₂, EE/hexane indifferent ratios such as 1:2) and the product (I) is in this wayobtained.

1.2 Method B:

The acid of general formula (III) (1 equivalent) and the amine ofgeneral formulae (II) (1.1 equivalents) are dissolved in dichloromethane(1 mmol of acid in 6 ml) and mixed with EDCI (1.5 equivalents), HOBt(1.4 equivalents) and triethylamine (3 equivalents) at 0° C. Thereaction mixture is stirred for 20 h at room temperature and the crudeproduct is purified by means of column chromatography (SiO₂, n-hexane/EEin different ratios such as 2:1) and (I) is in this way obtained.

1.3 Method C:

The acid of general formula (III) (1 equivalent) is first mixed with achlorinating agent, preferably with thionyl chloride and the mixtureobtained in this way is boiled under reflux and the acid (III) is inthis way converted into the corresponding acid chloride (IV). The amineof general formulae (II) (1.1 equivalents) is dissolved indichloromethane (1 mmol of acid in 6 ml) and mixed with triethylamine (3equivalents) at 0° C. The reaction mixture is stirred for 20 h at roomtemperature and the crude product is purified by means of columnchromatography (SiO₂, n-hexane/EE in different ratios such as 2:1) and(I) is in this way obtained.

1.4 Method D:

The phenyl ester (IVa) obtained (1 equivalent) and the correspondingamine (II) (1.1 equivalents) are dissolved in THF (10 mmol of thereaction mixture in 120 ml) and stirred for 16 h at room temperatureafter addition of DBU (1.5 equivalents). After removal of the solventunder vacuum, the residue obtained is purified by means of flashchromatography (SiO₂, EE/hexane in different ratios such as 1:1) and (I)is in this way obtained.

The following exemplary compounds I-56, 66-80, 117-121, 124-125,127-138, 140-143 and 145-147 were obtained using one of the methodsdescribed hereinbefore.

1 N-((3-tert-butyl-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(methylsulphonamido)phenyl)propanamide 2(S)-N-((3-tert-butyl-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(methylsulphonamido)phenyl)propanamide 3N-((3-tert-butyl-1-methyl-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(methylsulphonamido)phenyl)propanamide 4(S)-N-((3-tert-butyl-1-methyl-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(methylsulphonamido)phenyl)propanamide 5N-((3-tert-butyl-1-hexyl-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(methylsulphonamido)phenyl)propanamide 6(S)-N-((3-tert-butyl-1-hexyl-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(methylsulphonamido)phenyl)propanamide 7N-((3-tert-butyl-1-cyclohexyl-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(methylsulphonamido)phenyl)propanamide 8(S)-N-((3-tert-butyl-1-cyclohexenyl-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(methylsulphonamido)phenyl)propanamide 92-(3-fluoro-4-(methylsulphonamido)phenyl)-N-((3-methyl-1-phenyl-1H-pyrazol-5-yl)methyl)propanamide 10N-((3-chloro-1-phenyl-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(methylsulphonamido)phenyl)propanamide 112-(3-fluoro-4-(methylsulphonamido)phenyl)-N-((3-(4-fluorophenyl)-1-phenyl-1H-pyrazol-5-yl)methyl)propanamide 12N-((3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(methylsulphonamido)phenyl)propanamide 13N-((3-tert-butyl-1-(4-tert-butylphenyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(methylsulphonamido)phenyl)propanamide 14N-((3-tert-butyl-1-(4-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(methylsulphonamido)phenyl)propanamide 15(S)-N-((3-tert-butyl-1-(4-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(methylsulphonamido)phenyl)propanamide 16N-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(methylsulphonamido)phenyl)propanamide 17(S)-N-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(methylsulphonamido)phenyl)propanamide 18N-((3-tert-butyl-1-(3-chloro-4-fluorophenyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(methylsulphonamido)phenyl)propanamide 19(E)-N-((3-tert-butyl-1-(4-methylstyryl)-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(methylsulphonamido)phenyl)propanamide 20N-((3-tert-butyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(methylsulphonamido)phenyl)propanamide 21N-((1-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4- (methylsulphonamido)phenyl)propanamide 22(R)-N-((1-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4- (methylsulphonamido)phenyl)propanamide 23(S)-N-((1-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4- (methylsulphonamido)phenyl)propanamide 24N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4- (methylsulphonamido)phenyl)propanamide 25(R)-N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4- (methylsulphonamido)phenyl)propanamide 26(S)-N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4- (methylsulphonamido)phenyl)propanamide 27N-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2-(3-methoxy-4-(methylsulphonamido)phenyl)propanamide 28N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(3-methoxy-4- (methylsulphonamido)phenyl)propanamide 29N-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2-(3,5-difluoro-4-(methylsulphonamido)phenyl)propanamide 30N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(3,5-difluorophenyl)propanamide 312-(4-bromo-3-fluorophenyl)-N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)propanamide 32N-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2-(4-isobutylphenyl)propanamide 33N-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(methylsulphonamidomethyl)phenyl)propanamide 34N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(furan-3-yl)phenyl)propanamide 35N-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2-(2-fluorobiphenyl-4-yl)propanamide 36N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(4-(1,2-dihydroxyethyl)-3-fluorophenyl)propanamide 374-(1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylamino)-1-oxopropan-2-yl)-2-fluorobenzamide 384-(1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylamino)-1-oxopropan-2-yl)-N-ethylbenzamide 394-(1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylamino)-1-oxopropan-2-yl)-2-fluoro-N-phenylbenzamide 404-(1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylamino)-1-oxopropan-2-yl)-N-(4-fluorophenyl)benzamide 414-(1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylamino)-1-oxopropan-2-yl)-N-(4-(trifluoromethyl)phenyl)benzamide 424-(1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylamino)-1-oxopropan-2-yl)-N-(pyridin-4-yl)benzamide 43N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(4-(trifluormethoxy)phenyl)propanamide 44N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(3,5-dibromo-4-hydroxyphenyl)acetamide 45N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(3,5-dibromo-4-hydroxyphenyl)propanamide 46N-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2-(3,5-difluoro-4-hydroxyphenyl)propanamide 47N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(3,5-difluoro-4-methoxyphenyl)propanamide 48N-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2-(4-methoxy-3,5-dimethylphenyl)acetamide 49N-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2-(4-(N,N-dimethylsulphamoyl)-3-fluorophenyl)propanamide 50N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(4-(4-chlorophenylamino)phenyl)propanamide 51N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(4-(4-methoxyphenylamino)phenyl)propanamide 522-(4-amino-3,5-difluorophenyl)-N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)propanamide 532-(4-acetamido-3-fluorophenyl)-N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)propanamide 54N-(4-(1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylamino)-1-oxopropan-2-yl)-2-fluorophenyl)benzamide 55N-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2-[4-(1,1-dioxidoisothiazolidin-2-yl)-3-fluorophenyl]propanamide 56N-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2-(4-(N,N-dimethylsulphamoyl)-3-fluorophenyl)propanamide 66N-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(methylsulphonamido)phenyl)-2-(3- fluorophenyl)acetamide 67N-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2-cyclohexyl-2-(3-fluoro-4-(methylsulphonamido)phenyl)acetamide 68N-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(methylsulphonamido)phenyl)-2-p-tolylacetamide 69N-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2-(3-chloro-4-(methylthio)phenyl)propanamide 70N-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2-(3-chloro-4-(methylsulphonyl)phenyl)propanamide 71N-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(methylthio)phenyl)propanamide 72N-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(methylsulphonyl)phenyl)propanamide 73N-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluorophenyl)acetamide 74N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluorophenyl)acetamide 75N-[[5-tert-butyl-2-(3-chlorophenyl)-2H-[1,2,4]triazol-3-yl]-methyl]-2-[3-fluoro-4-(methanesulphonamido)phenyl]propionamide 76N-[[2-(3-chlorophenyl)-5-(trifluoromethyl)-2H-[1,2,4]triazol-3-yl]-methyl]-2-[3-fluoro-4- (methanesulphonamido)phenyl]propionamide 77N-[(5-tert-butyl-2-cyclohexyl-2H-[1,2,4]triazol-3-yl)-methyl]-2-[3-fluoro-4-(methanesulphonamido)phenyl]propionamide 78N-[[2-cyclohexyl-5-(trifluoromethyl)-2H-[1,2,4]triazol-3-yl]-methyl]-2-[3-fluoro-4-(methanesulphonamido)phenyl]propionamide 79N-[(5-tert-butyl-2-pyridin-3-yl-2H-[1,2,4]triazol-3-yl)-methyl]-2-[3-fluoro-4-(methanesulphonamido)phenyl]propionamide 802-[3-fluoro-4-(methanesulphonamido)phenyl]-N-[[2-pyridin-3-yl-5-(trifluoromethyl)-2H-[1,2,4]triazol-3-yl]-methyl]propionamide 117N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluorophenyl)-2-methylpropanamide 118N-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-1-(3-fluorophenyl)cyclopropancarboxamide 119N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-1-(3-fluorophenyl)cyclobutancarboxamide 120N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-1-(3-fluorophenyl)cyclopentancarboxamide 121N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-1-(3-fluorophenyl)cyclohexancarboxamide 124N-((1-(3-chloro-4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4- (methylsulfonylmethyl)phenyl)propanamide 125N-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2-(4-cyclopropyl-3-fluorophenyl)propanamide 127N-((3-tert-butyl-1-(pyridin-2-yl)-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(methylsulfonamidmethyl)phenyl)propanamide 128N-((1-(3-chlorophenyl)-3-cyclopropyl-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(methylsulfonylmethyl)phenyl)propanamide 1292-(3-fluoro-4-(methylsulfonamidmethyl)phenyl)-N-((1-(pyridin-2-ylmethylamino)-3-(trifluoromethyl)-1H-pyrazol-5- yl)methyl)propanamide130 N-((1-(3-chlorophenyl)-4-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluorophenyl)acetamide 1312-(3-fluorophenyl)-N-((1-pentyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)acetamide 1322-(3-fluorophenyl)-N-((1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)acetamide 133N-((3-tert-butyl-1-(2,2,2-trifluoroethylamino)-1H-pyrazol-5-yl)methyl)-2-(3-fluorophenyl)acetamide 134N-((1-(3-chlorophenyl)-4-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(methylsulfonamidmethyl)phenyl)propanamide 135N-((3-tert-butyl-1-(3-chlorophenyl)-1H-1,2,4-triazol-5-yl)methyl)-2-(3-fluorophenyl)acetamide 1362-(3-fluorophenyl)-N-((1-(pyridin-3-yl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)acetamide 137N-((1-cyclohexyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(methylsulfonamidmethyl)phenyl)propanamide 1382-(3-fluoro-4-(methylsulfonamidmethyl)phenyl)-N-((1-(tetrahydro-2H-pyran-4-yl)-3-(trifluoromethyl)-1H-pyrazol-5- yl)methyl)propanamide140 N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(trifluoromethyl)phenyl)acetamide 141N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(trifluoromethyl)phenyl)propanamide 142N-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-((2-methoxyethoxy)methyl)phenyl)propanamide 1434-(1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylamino)-1-oxopropan-2-yl)-N-phenylbenzamide 145N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(methylsulfonamid)phenyl)-3- phenylpropanamide146 N-(5-((2-(3-fluorophenyl)acetamide)methyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzamide 147N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(3,5-difluoro-4-hydroxyphenyl)acetamide

2. Preparation of Ureas (A=N)

General directions for reacting amines of general formula (II) or (VI)with phenyl chloroformate to form compounds of formula (V) or (VIa)(step j07 and step v1, respectively) and subsequent reaction ofcompounds of formula (V) with amines of general formula (VI) or ofcompounds of formula (VIa) with amines of general formula (II) to formcompounds of general formula (I), wherein A=N, as in scheme 1a and 1c(step j08 and step v2, respectively):

Step j07/step v1: The amine of general formula (II) or (VI) (1equivalent) is placed in dichloromethane (10 mmol of amine in 70 ml) andphenyl chloroformate (1.1 equivalents) is added thereto at roomtemperature and the mixture is stirred for 30 min. After removal of thesolvent under vacuum, the residue is purified by means of flashchromatography (SiO₂, diethyl ether/hexane in different ratios such as1:2) and (V) or (VIa) is in this way obtained.

Step j08/step v2: The carbamic acid phenyl ester (V) or (VIa) obtained(1 equivalent) and the corresponding amine (VI) or (II) (1.1equivalents) are dissolved in THF (10 mmol of the reaction mixture in120 ml) and stirred for 16 h at room temperature after addition of DBU(1.5 equivalents). After removal of the solvent under vacuum, theresidue obtained is purified by means of flash chromatography (SiO₂,EE/hexane in different ratios such as 1:1) and (I) is in this wayobtained.

The following exemplary compounds 57-65, 122-123, 126, 139 and 144 wereobtained using one of the methods described hereinbefore.

57 1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(3,5-difluorophenyl)urea 581-(4-bromo-3-fluorophenyl)-3-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)urea 591-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(4-(trifluoromethyl)phenyl)urea 601-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(4-(difluormethoxy)phenyl)urea 611-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(3,5-difluoro-4-methoxyphenyl)urea 621-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(4-methoxy-3,5-dimethylphenyl)urea 631-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(3-fluoro-4-(methylsulphonyl)phenyl)urea 641-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(4-(phenylamino)phenyl)urea 654-(3-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)ureido)-N-(4-fluorophenyl)benzamide 1221-((3-tert-butyl-1-(4-fluorophenyl)-1H-pyrazol-5-yl)methyl)-3-(3-fluorophenyl)urea 1233-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-1-(3-fluorophenyl)-1-methylurea 1261-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(4-cyclopropyl-3-fluorophenyl)urea 1391-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(4-(cyclopropylethynyl)-3-fluorophenyl)urea 1441-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(3-fluoro-4-morpholinphenyl)urea

The methods illustrated hereinbefore for synthesising the compoundsaccording to the invention enable a person skilled in the art also tosynthesise the following exemplary compounds 81-116:

81 N-[[5-tert-butyl-2-(6-chloropyridin-2-yl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(methanesulphonamido)phenyl]propionamide 82N-[[5-tert-butyl-2-(3,3-difluorocyclobutanecarbonyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4- (methanesulphonamido)phenyl]propionamide 83N-[[2-(3-chlorophenyl)-4-methyl-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4- (methanesulphonamido)phenyl]propionamide 84N-[[2-(dipropylamino)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[4-(methanesulphonamido)- 3-methoxyphenyl]propionamide 85N-[[2-(dipropylamino)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(hydroxymethyl)phenyl]propionamide 86N-[[2-(dipropylamino)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4- (methanesulphonamido)phenyl]propionamide 87N-[[2-(dipropylamino)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-(3-fluorophenyl)acetamide 884-[1-[[2-(dipropylamino)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methylcarbamoyl]ethyl]-2-fluorobenzamide 894-[1-[[2-(dipropylamino)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methylcarbamoyl]ethyl]-N-pyridin-2-yl-benzamide 902-[3-fluoro-4-(hydroxymethyl)phenyl]-N-[[2-piperidin-1-yl-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]propionamide 912-[3-fluoro-4-(2-hydroxyethyl)phenyl]-N-[[2-piperidin-1-yl-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]propionamide 922-[3-fluoro-4-(methanesulphonamido)phenyl]-N-[[2-pipendin-1-yl-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]propionamide 932-[4-(methanesulphonamido)-3-methoxyphenyl]-N-[[2-pipendin-1-yl-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]propionamide 942-[4-(1,2-dihydroxyethyl)-3-fluorophenyl]-N-[[2-piperidin-1-yl-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]propionamide 952-(3-fluorophenyl)-N-[[2-piperidin-1-yl-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]acetamide 962-fluoro-4-[1-[[2-pipendin-1-yl-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methylcarbamoyl]ethyl]benzamide 972-[3-fluoro-4-(methanesulphonamido)phenyl]-N-[[2-[(4-fluorophenyl)methylmethylamino]-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]propionamide 98N-[[5-tert-butyl-2-(2,2,2-trifluoroethylamino)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4- (methanesulphonamido)phenyl]propionamide 99N-[[2-butoxy-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(hydroxymethyl)phenyl]propionamide 100N-[[2-butoxy-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(methanesulphonamido)phenyl]propionamide 101N-[[2-butoxy-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[4-(methanesulphonamido)-3-methoxyphenyl]propionamide 102N-[(2-butoxy-5-tert-butyl-2H-pyrazol-3-yl)-methyl]-2-(3-fluorophenyl)acetamide; 103N-[[2-cyclopentyloxy-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4- (methanesulphonamido)phenyl]propionamide 104N-[[2-cyclopentyloxy-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[4-(methanesulphonamido)- 3-methoxyphenyl]propionamide 1052-(3-fluorophenyl)-N-[[2-[(4-methoxyphenyl)methoxy]-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]acetamide 106N-[[5-tert-butyl-2-(3-cyano-5-fluorophenoxy)-2H-pyrazol-3-yl]-methyl]-2-(3-fluorophenyl)acetamide 107N-[[2-(cyclohexylsulphanyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4- (methanesulphonamido)phenyl]propionamide; 108N-[[2-(benzenesulphonyl)-5-tert-butyl-2H-pyrazol-3-yl]-methyl]-2-(3-fluorophenyl)acetamide 109N-[[2-cyclohexyl-5-(trifluoromethyl)-2H-[1,2,4]triazol-3-yl]-methyl]-2-[4-(methanesulphonamido)-3- methoxyphenyl]propionamide 110N-[[2-cyclohexyl-5-(trifluoromethyl)-2H-[1,2,4]triazol-3-yl]-methyl]-2-(3-fluorophenyl)acetamide 1114-[1-[[2-cyclohexyl-5-(trifluoromethyl)-2H-[1,2,4]triazol-3-yl]-methylcarbamoyl]ethyl]-2-fluorobenzamide 1122-[3-fluoro-4-(hydroxymethyl)phenyl]-N-[[2-hexyl-5-(trifluoromethyl)-2H-[1,2,4]triazol-3-yl]-methyl]propionamide 1134-[1-[[2-cyclobutyl-5-(trifluoromethyl)-2H-[1,2,4]triazol-3-yl]-methylcarbamoyl]ethyl]-2-fluorobenzamide 114N-[[5-tert-butyl-2-(3,3-difluorocyclobutanecarbonyl)-2H-[1,2,4]triazol-3-yl]-methyl]-2-[3-fluoro-4-(methanesulphonamido)phenyl]propionamide 115N-[[5-tert-butyl-2-(3-cyano-5-fluorophenoxy)-2H-[1,2,4]triazol-3-yl]-methyl]-2-(3-fluorophenyl)acetamide 116N-[[2-(benzenesulphonyl)-5-tert-butyl-2H-[1,2,4]triazol-3-yl]-methyl]-2-(3-fluorophenyl)acetamide

Mass spectrometric data are cited hereinafter by way of example for thefollowing exemplary compounds:

Exemplary compound [M + H] 1 397.2 2 397.2 3 411.2 4 411.2 5 481.1 6481.1 7 479.3 8 477.1 12 478.2 13 529.3 14 507.0 15 507.0 16 507.2 17507.0 18 525.2 19 513.2 20 503.2 21 518.9 22 518.9 23 518.9 24 518.9 25518.9 26 518.9 27 519.3 28 531.2 29 525.3 30 444.0 33 521.3 39 545.4 40545.0 41 595.3 47 474.3 49 521.3 55 533.3 56 521.3 61 449.3 74 412.1 117440.2 118 426.3 119 452.2 120 466.3 122 385.1 123 427.0 125 454.0 126452.9 127 488.2 128 504.9 129 529.3 130 426.3 131 372.1 132 422.1 133387.3 134 546.9 135 401.3 137 505.0 139 477.2 141 493.9 142 502.0 143527.0 144 486.1 147 446.0

Pharmacological Data

The affinity of the compounds according to the invention for thevanilloid receptor 1 (VR1/TRPV1 receptor) was determined as describedhereinbefore (pharmacological methods I and II respectively).

The compounds according to the invention of the above-indicated formula(I) display outstanding affinity to the VR1/TRPV1 receptor (Table 1.).

In Table 1 the abbreviations below have the following meanings:

Cap=capsaicinAG=agonistpAG=partial agonistpH=after pH stimulusNADA=N-arachidonoyl dopamineNE=no effectFTm=formalin test carried out on mice

The value after the “@” symbol indicates the concentration at which theinhibition (as a percentage) was respectively determined.

TABLE 1 Compound K_(i) IC₅₀ K_(i) IC₅₀ according K_(i) (rat) (humanbeing) (human being) K_(i) (rat) (human being) (human being) to Example[nM] Cap [nM] Cap hVR1 [nM], pH [nM] NADA [nM] NADA [nM], 45° C. FTm 125% @ 5 μM NE NE 2 25% @ 5 μM NE NE 3 14% @ 5 μM 12% @ 5 μM NE 4 20% @ 5μM  9% @ 5 μM NE 5 76% @ 1 μM 50.2 36% @ 10 μM 4.99 282 6 14.5 27.7 13%@ 10 μM 7 0.35 21.6 NE 12 5.9 8 40% @ 10 μM 13 25.9 (15) 75.2 (49) 147.2 3.7 25% @ 10 μM 15 2.5 2.1  14% @ 5 μM 16 0.2 0.3 NE 0.03 0.04 35% @0.625 μM  17 0.1 0.1 37% @ 10 μM 18 0.5 31% @ 10 μM 0.22 7.0 19 819 44%@ 1 μM NE 20 2834 55% @ 1 μM NE 21 1.2 0.3 179 0.12 27.0 22 42.7 31.742% @ 10 μM 23 0.4 0.3 47.1 16.13 24 0.4 0.3 39.2 25 5.1 26.5 2,585 260.1 0.1 8.0 0.1 8.05 27 1.2 2.2 NE 0.12 28 0.4 16 665 29 1.2 42% @ 10 μM0.08   34% @ 2 μM 30 6.3 33 4.0 39 7.2 40 0.8 41 85 47 17 49 AG AG AG AG55 114 NE 56 AG AG AG AG 61 AG 73 AG 74 85 51.8 49 12% @ 2.5 μM 1 po FTm13% 117 56 118 AG 119 107 120  6% @ 1 μM 122 AG 123 44% @ 5 μM 125 AG126 31.4 127 58.1 128 16.3 129 63.6 130 112 131 58% @ 5 μM 132 34% @ 5μM 133 12% @ 5 μM 134 2.5 546 135 24% @ 5 μM 137 65.1 139 AG 141 25.513.6 28% @ 2.5 μM 142 AG 143 56% @ 1 μM 144 AG 147 26

1-11. (canceled)
 12. A method for treatment or prophylaxis of one ormore disorders comprising administering to a patient at least onesubstituted compound of general formula (I)

wherein X represents CR³ or N, wherein R³ represents H; C₁₋₁₀ alkyl,saturated or unsaturated, branched or unbranched, unsubstituted or mono-or polysubstituted; A represents N or CR^(5b), n represents 1, 2, 3 or4; R⁰ represents C₁₋₁₀ alkyl, saturated or unsaturated, branched orunbranched, unsubstituted or mono- or polysubstituted; C₃₋₁₀ cycloalkylor heterocyclyl, respectively saturated or unsaturated, unsubstituted ormono- or polysubstituted; aryl or heteroaryl, respectively unsubstitutedor mono- or polysubstituted; C₃₋₁₀ cycloalkyl or heterocyclyl bridgedvia C₁₋₈ alkyl, respectively saturated or unsaturated, unsubstituted ormono- or polysubstituted, wherein the alkyl chain can be respectivelybranched or unbranched, saturated or unsaturated, unsubstituted, mono-or polysubstituted; or aryl or heteroaryl bridged via C₁₋₈ alkyl,respectively unsubstituted or mono- or polysubstituted, wherein thealkyl chain can be respectively branched or unbranched, saturated orunsaturated, unsubstituted, mono- or polysubstituted; R¹ representsC₁₋₁₀ alkyl, saturated or unsaturated, branched or unbranched,unsubstituted or mono- or polysubstituted; C₃₋₁₀ cycloalkyl¹ orheterocyclyl¹, respectively saturated or unsaturated, unsubstituted ormono- or polysubstituted; aryl or heteroaryl, respectively unsubstitutedor mono- or polysubstituted; C₃₋₁₀ cycloalkyl¹ or heterocyclyl¹ bridgedvia C₁₋₈ alkyl, respectively saturated or unsaturated, unsubstituted ormono- or polysubstituted, wherein the alkyl chain can be respectivelybranched or unbranched, saturated or unsaturated, unsubstituted, mono-or polysubstituted; or aryl or heteroaryl bridged via C₁₋₈ alkyl,respectively unsubstituted or mono- or polysubstituted, wherein thealkyl chain can be respectively branched or unbranched, saturated orunsaturated, unsubstituted, mono- or polysubstituted; C(═O)—R⁰;C(═O)—OH; C(═O)—OR⁰; C(═O)—NHR⁰; C(═O)—N(R⁰)₂; OH; O—R⁰; SH; S—R⁰;S(═O)₂—R⁰; S(═O)₂—OR⁰; S(═O)₂—NHR⁰; S(═O)₂—N(R⁰)₂; NH₂; NHR⁰; N(R⁰)₂;NH—S(═O)₂—R⁰; N(R⁰)(S(═O)₂—R⁰); or SCl₃; R² represents H; R⁰; F; I; CN;NO₂; OH; SH; CF₃; CF₂H; CFH₂; CF₂Cl; CFCl₂; CH₂CF₃; OCF₃; OCF₂H; OCFH₂;OCF₂Cl; OCFCl₂; SCF₃; SCF₂H; SCFH₂; SCF₂Cl; SCFCl₂; S(═O)₂—CF₃;S(═O)₂—CF₂H; S(═O)₂—CFH₂; or SF₅; R⁴ represents H; F; Cl; Br; I; OH;C₁₋₁₀ alkyl, saturated or unsaturated, branched or unbranched,unsubstituted or mono- or polysubstituted; R^(5a) represents H; OH;C₁₋₁₀ alkyl, saturated or unsaturated, branched or unbranched,unsubstituted or mono- or polysubstituted; R^(5b) represents H or R⁰; orR^(5a) and R^(5b) form together with the carbon atom connecting them aC₃₋₁₀ cycloalkyl or a heterocyclyl, respectively saturated orunsaturated, unsubstituted or mono- or polysubstituted; R⁶, R⁷, R⁹ andR¹⁰ each independently of one another represent H; F; Cl; Br; I; NO₂;CN; CF₃; CF₂H; CFH₂; CF₂Cl; CFCl₂; R⁰; C(═O)H; C(═O)R⁰; CO₂H; C(═O)OR⁰;CONH₂; C(═O)NHR⁰; C(═O)N(R⁰)₂; OH; OCF₃; OCF₂H; OCFH₂; OCF₂Cl; OCFCl₂;OR⁰; O—C(═O)—R⁰; O—C(═O)—O—R⁰; O—(C═O)—NH—R⁰; O—C(═O)—N(R⁰)₂;O—S(═O)₂—R⁰; O—S(═O)₂OH; O—S(═O)₂OR⁰; O—S(═O)₂NH₂; O—S(═O)₂NHR⁰;O—S(═O)₂N(R⁰)₂; NH₂; NH—R⁰; N(R⁰)₂; NH—C(═O)—R⁰; NH—C(═O)—O—R⁰;NH—C(═O)—NH₂; NH—C(═O)—NH—R⁰; NH—C(═O—N(R⁰)NR⁰—C(═O)—R⁰; NR⁰—C(═O)—O—R⁰;NR⁰—C(═O)—NH₂; NR⁰—C(═O)—NH—R⁰; NR⁰—C(═O)—N(R⁰)₂; NH—S(═O)₂OH;NH—S(═O)₂R⁰; NH—S(═O)₂OR⁰; NH—S(═O)₂NH₂; NH—S(═O)₂NHR⁰; NH—S(═O)₂N(R⁰)₂;NR⁰—S(═O)₂OH; NR⁰—S(═O)₂R⁰; NR⁰—S(═O)₂OR⁰; NR⁰—S(═O)₂NH₂;NR⁰—S(═O)₂NHR⁰; NR⁰—S(═O)₂N(R⁰)₂; SH; SCF₃; SCF₂H; SCFH₂; SCF₂Cl;SCFCl₂; SR⁰; S(═O)R⁰; S(═O)₂R⁰; S(═O)₂OH; S(O)₂OR²; S(═O)₂NH₂;S(═O)₂NHR⁰; or S(═O)₂N(R⁰)₂; R⁸ represents H; F; Cl; Br; I; NO₂; CN;CF₃; CF₂H; CFH₂; CF₂Cl; CFCl₂; R⁰; C(═O)H; C(═O)R⁰; CO₂H; C(═O)OR⁰;CONH₂; C(═O)NHR⁰; C(═O)N(R⁰)₂; OH; OCF₃; OCF₂H; OCFH₂; OCF₂Cl; OCFCl₂;OR⁰; O—C(═O)—R⁰; O—C(═O)—O—R⁰; O—(C═)—NH—R⁰; O—C(═O)—N(R⁰)₂; O—S(λO)₂R⁰;O—S(═O)₂OH; O—S(═O)₂OR⁰; O—S(═O)₂NH₂; O—S(═O)₂NHR⁰; O—S(═O)₂N(R⁰)₂; NH₂;NH—R⁰; N(R⁰)₂; NH—C(═O)—R⁰; NH—C(═O)—O—R⁰; NH—C(═O)—NH₂; NH—C(═O)—NH—R⁰;NH—C(═O—N(R⁰)₂; NR⁰—C(═O)—R⁰; NR⁰—C(═O)—R⁰; NR⁰—C(═O)—NH₂;NR⁰—C(═O)—NH—R⁰; NR⁰—C(═O)—N(R⁰)₂; NH—S(═O)₂OH; NH—S(═O)₂R⁰;NH—S(λO)₂OR⁰; NH—S(═O)₂NH₂; NH—S(═O)₂NHR⁰; NH—S(═O)₂N(R⁰)₂;NR⁰—S(═O)₂OH; NR⁰—S(═O)₂R⁰; NR⁰—S(═O)₂OR⁰; NR⁰—S(═O)₂NH₂;NR⁰—S(═O)₂NHR⁰; NR⁰—S(═O)₂N(R⁰)₂; SH; SCF₃; SCF₂H; SCFH₂; SCF₂Cl;SCFCl₂; SR⁰; S(═O)R⁰; S(═O)₂R⁰; S(═O)₂OH; S(═O)₂OR⁰; S(═O)₂NH₂;S(═O)₂NHR⁰; or S(═O)₂N(R⁰)₂; wherein, if R⁸ denotes R⁰ and R⁰ representsheteroaryl, said heteroaryl is selected from the group consisting ofbenzofuranyl, benzoimidazolyl, benzothienyl, benzothiadiazolyl,benzothiazolyl, benzotriazolyl, benzooxazolyl, benzooxadiazolyl,quinazolinyl, quinoxalinyl, carbazolyl, quinolinyl, dibenzofuranyl,dibenzothienyl, furyl (furanyl), imidazothiazolyl, indazolyl,indolizinyl, indolyl, isoquinolinyl, isoxazoyl, isothiazolyl, indolyl,naphthyridinyl, oxazolyl, oxadiazolyl, phenazinyl, phenothiazinyl,phthalazinyl, pyrazolyl, pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl),pyrrolyl, pyridazinyl, pyrimidinyl, pyrazinyl, purinyl, phenazinyl,thienyl (thiophenyl), triazolyl, tetrazolyl, thiazolyl, thiadiazolyl andtriazinyl; in which “substituted alkyl”, “substituted heterocyclyl” and“substituted cycloalkyl” relate, with respect to the correspondingresidues, to the substitution of one or more hydrogen atoms eachindependently of one another by F; Cl; Br; I; NO₂; CN; ═O; ═NH;═C(NH₂)₂; CF₃; CF₂H; CFH₂; CF₂Cl; CFCl₂; R⁰; C(═O)H; C(═O)R⁰; CO₂H;C(═O)OR⁰; CONH₂; C(═O)NHR⁰; C(═O)N(R⁰)₂; OH; OCF₃; OCF₂H; OCFH₂; OCF₂Cl;OCFCl₂; OR⁰; O—C(═O)—R⁰; O—C(═O)—O—R⁰; O—(C═O)—NH—R⁰; O—C(═O)—N(R⁰)₂;O—S(═O)—R⁰; O—S(═O)₂OH; O—S(═O)₂OR⁰; O—S(═O)₂NH₂; O—S(═O)₂NHR⁰;O—S(═O)₂N(R⁰)₂; NH₂; NH—R⁰; N(R⁰)₂; NH—C(═O)—R⁰; NH—C(═O)—O—R⁰;NH—C(═O)—NH₂; NH—C(═O)—NH—R⁰; NH—C(═O)—N(R⁰)₂; NR⁰—C(═O)—R⁰;NR⁰—C(═O)—O—R⁰; NR⁰—C(═O)—NH₂; NR⁰—C(═O)—NH—R⁰; NR⁰—C(═O)—N(R⁰)₂;NH—S(═O)₂OH; NH—S(═O)₂R⁰; NH—S(═O)₂OR⁰; NH—S(═O)₂NH₂; NH—S(═O)₂NHR⁰;NH—S(═O)₂N(R⁰)₂; NR⁰—S(═O)₂OH; NR⁰—S(═O)₂R⁰; NR⁰—S(═O)₂OR⁰;NR⁰—S(═O)₂NH₂; NR⁰—S(═O)₂NHR⁰; NR⁰—S(═O)₂N(R⁰)₂; SH; SCF₃; SCF₂H; SCFH₂;SCF₂Cl; SCFCl₂; SR⁰; S(═O)R⁰; S(═O)₂R⁰; S(═O)₂OH; S(═O)₂OR⁰; S(═O)₂NH₂;S(═O)₂NHR⁰; or S(═O)₂N(R⁰)₂; in which “substituted cycloalkyl¹” and“substituted heterocyclyl¹” relate, with respect to the correspondingresidues, to the substitution of one or more hydrogen atoms eachindependently of one another by F; Cl; Br; I; NO₂; CN; ═O; ═C(NH₂)₂;CF₃; CF₂H; CFH₂; CF₂Cl; CFCl₂; R⁰; C(═O)H; C(═O)R⁰; CO₂H; C(═O)OR⁰;CONH₂; C(═O)NHR⁰; C(═O)N(R⁰)₂; OH; OCF₃; OCF₂H; OCFH₂; OCF₂Cl; OCFCl₂;OR⁰; O—C(═O)—R⁰; O—C(═O)—O—R⁰; O—(C═O)—NH—R⁰; O—C(═O)—N(R⁰)₂;O—S(═O)₂—R⁰; O—S(═O)₂OH; O—S(═O)₂OR⁰; O—S(═O)₂NH₂; O—S(═O)₂NHR⁰;O—S(═O)₂N(R⁰)₂; SH; SCF₃; SCF₂H; SCFH₂; SCF₂Cl; SCFCl₂; SR⁰; S(═O)R⁰;S(═O)₂R⁰; S(═O)₂OH; S(═O)₂OR⁰; S(═O)₂NH₂; S(═O)₂NHR⁰; or S(═O)₂N(R⁰)₂;in which “substituted aryl” relates, with respect to the correspondingresidues, to the substitution of one or more hydrogen atoms eachindependently of one another by F; Cl; Br; I; NO₂, CF₃; CF₂H; CFH₂;CF₂Cl; CFCl₂; R⁰; C(═O)H; C(═O)R⁰; CO₂H; C(═O)OR⁰; CONH₂; C(═O)NHR⁰;C(═O)N(R⁰)₂; OH; OCF₃; OCF₂H; OCFH₂; OCF₂Cl; OCFCl₂; OR⁰; O—C(═O)—R⁰;O—C(═O)—O—R⁰; O—(C═O)—NH—R⁰; O—C(═O)—N(R⁰)₂; O—S(═O)₂—R⁰; O—S(═O)₂OH;O—S(═O)₂OR⁰; O—S(═O)₂NH₂; O—S(═O)₂NHR⁰; O—S(═O)₂N(R⁰)₂; NH₂; NH—R⁰;N(R⁰)₂; NH—C(═O)—R⁰; NH—C(═O)—O—R⁰; NH—C(═O)—NH₂; NH—C(═O)—NH—R⁰;NH—C(═O)—N(R⁰)₂; NR⁰—C(═O)—R⁰; NR⁰—C(═O)—O—R⁰; NR⁰—C(═O)—NH₂;NR⁰—C(═O)—NH—R⁰; NR⁰—C(═O)—N(R⁰)₂; NH—S(═O)₂OH; NH—S(═O)₂R⁰;NH—S(═O)₂OR⁰; NH—S(═O)₂NH₂; NH—S(═O)₂NHR⁰; NH—S(═O)₂N(R⁰)₂;NR⁰—S(═O)₂OH; NR⁰—S(═O)₂R⁰; NR⁰—S(═O)₂OR⁰; NR⁰—S(═O)₂NH₂;NR⁰—S(═O)₂NHR⁰; NR⁰—S(═O)₂N(R⁰)₂; SH; SCF₃; SCF₂H; SCFH₂; SCF₂Cl;SCFCl₂; SR⁰; S(═O)R⁰; S(═O)₂R⁰; S(═O)₂OH; S(═O)₂OR⁰; S(═O)₂NH₂;S(═O)₂NHR⁰; or S(═O)₂N(R⁰)₂; in which ““substituted heteroaryl” relates,with respect to the corresponding residues, to the substitution of oneor more hydrogen atoms each independently of one another by F; Cl; Br;I; NO₂; CN; CF₃; CF₂H; CFH₂; CF₂Cl; CFCl₂; R⁰; C(═O)H; C(═O)R⁰; CO₂H;C(═O)OR⁰; CONH₂; C(═O)NHR⁰; C(═O)N(R⁰)₂; OH; OCF₃; OCF₂H; OCFH₂; OCF₂Cl;OCFCl₂; OR⁰; O—C(═O)—R⁰; O—C(═O)—O—R⁰; O—(C═O)—NH—R⁰; O—C(═O)—N(R⁰)₂;O—S(═O)₂—R⁰; O—S(═O)₂OH; O—S(═O)₂OR⁰; O—S(═O)₂NH₂; O—S(═O)₂NHR⁰;O—S(═O)₂N(R⁰)₂; NH₂; NH—R⁰; N(R⁰)₂; NH—C(═O)—R⁰; NH—C(═O)—O—R⁰;NH—C(═O)—NH₂; NH—C(═O)—NH—R⁰; NH—C(═O)—N(R⁰)₂; NR⁰—C(═O)—R⁰;NR⁰—C(═O)—O—R⁰; NR⁰—C(═O)—NH₂; NR⁰—C(═O)—NH—R⁰; NR⁰—C(═O)—N(R⁰)₂;NH—S(═O)₂OH; NH—S(═O)₂R⁰; NH—S(═O)₂OR⁰; NH—S(═O)₂NH₂; NH—S(═O)₂NHR⁰;NH—S(═O)₂N(R⁰)₂; NR⁰—S(═O)₂OH; NR⁰—S(═O)₂R⁰; NR⁰—S(═O)₂OR⁰;NR⁰—S(═O)₂NH₂; NR⁰—S(═O)₂NHR⁰; NR⁰—S(═O)₂N(R⁰)₂; SH; SCF₃; SCF₃; SCF₂H;SCFH₂; SCF₂Cl; SCFCl₂; SR⁰; S(═O)R⁰; S(═O)₂R⁰; S(═O)₂OH; S(═O)₂OR⁰;S(═O)₂NH₂; S(═O)₂NHR⁰; or S(═O)₂N(R⁰)₂ in the form of an individualstereoisomer or the mixture thereof, the free compound and/or itsphysiologically compatible salts, wherein the one or more disorders isselected from the group consisting of pain; hyperalgesia; allodynia;causalgia; migraine; depression; nervous affection; axonal injuries;neurodegenerative disease; cognitive dysfunctions epilepsy; respiratorydiseases coughs; urinary incontinence; overactive bladder (OAB);disorders and/or injuries of the gastrointestinal tract; duodenalulcers; gastric ulcers; irritable bowel syndrome; strokes; eyeirritations; skin irritations; neurotic skin diseases; allergic skindiseases; psoriasis; vitiligo; herpes simplex; inflammation; diarrhoea;pruritus; osteoporosis; arthritis; osteoarthritis; rheumatic diseases;eating disorders; medication dependency; misuse of medication;withdrawal symptoms in medication dependency; development of toleranceto medication; drug dependency; misuse of drugs; withdrawal symptoms indrug dependency; alcohol dependency; misuse of alcohol and withdrawalsymptoms in alcohol dependency; for diuresis; for antinatriuresis; forinfluencing the cardiovascular system; for increasing vigilance; for thetreatment of wounds and/or burns; for the treatment of severed nerves;for increasing libido; for modulating movement activity; for anxiolysis;for local anaesthesia and/or for inhibiting undesirable side effects.13. A method for treatment or prophylaxis of one or more disorderscomprising administering to a patient at least one substituted compoundof general formula (I)

wherein X represents CR³ or N, wherein R³ represents H; Cl₁₋₁₀ alkyl,saturated or unsaturated, branched or unbranched, unsubstituted or mono-or polysubstituted; A represents N or CR^(5b), n represents 1, 2, 3 or4; R⁰ represents C₁₋₁₀ alkyl, saturated or unsaturated, branched orunbranched, unsubstituted or mono- or polysubstituted; C₃₋₁₀ cycloalkylor heterocyclyl, respectively saturated or unsaturated, unsubstituted ormono- or polysubstituted; aryl or heteroaryl, respectively unsubstitutedor mono- or polysubstituted; C₃₋₁₀ cycloalkyl or heterocyclyl bridgedvia C₁₋₈ alkyl, respectively saturated or unsaturated, unsubstituted ormono- or polysubstituted, wherein the alkyl chain can be respectivelybranched or unbranched, saturated or unsaturated, unsubstituted, mono-or polysubstituted; or aryl or heteroaryl bridged via C₁₋₈ alkyl,respectively unsubstituted or mono- or polysubstituted, wherein thealkyl chain can be respectively branched or unbranched, saturated orunsaturated, unsubstituted, mono- or polysubstituted; R¹ representsC₁₋₁₀ alkyl, saturated or unsaturated, branched or unbranched,unsubstituted or mono- or polysubstituted; C₃₋₁₀ cycloalkyl¹ orheterocyclyl¹, respectively saturated or unsaturated, unsubstituted ormono- or polysubstituted; aryl or heteroaryl, respectively unsubstitutedor mono- or polysubstituted; C₃₋₁₀ cycloalkyl¹ or heterocyclyl¹ bridgedvia C₁₋₈ alkyl, respectively saturated or unsaturated, unsubstituted ormono- or polysubstituted, wherein the alkyl chain can be respectivelybranched or unbranched, saturated or unsaturated, unsubstituted, mono-or polysubstituted; or aryl or heteroaryl bridged via C₁₋₈ alkyl,respectively unsubstituted or mono- or polysubstituted, wherein thealkyl chain can be respectively branched or unbranched, saturated orunsaturated, unsubstituted, mono- or polysubstituted; C(═O)—R⁰;C(═O)—OH; C(═O)—OR⁰; C(═O)—NHR⁰; C(═O)—N(R⁰)₂; OH; O—R⁰; SH; S—R⁰;S(═O)₂—R⁰; S(═O)₂—OR⁰; S(═O)₂—NHR⁰; S(═O)₂—N(R⁰)₂; NH₂; NHR⁰; N(R⁰)₂;NH—S(═O)₂—R⁰; N(R⁰)(S(═O)₂—R⁰); or SCl₃; R² represents H; R⁰; F; I; CN;NO₂; OH; SH; CF₃; CF₂H; CFH₂; CF₂Cl; CFCl₂; CH₂CF₃; OCF₃; OCF₂H; OCFH₂;OCF₂Cl; OCFCl₂; SCF₃; SCF₂H; SCFH₂; SCF₂Cl; SCFCl₂; S(═O)₂—CF₃;S(═O)₂—CF₂H; S(═O)₂—CFH₂; or SF₅; R⁴ represents H; F; Cl; Br; I; OH;C₁₋₁₀ alkyl, saturated or unsaturated, branched or unbranched,unsubstituted or mono- or polysubstituted; R^(5a) represents H; OH;C₁₋₁₀ alkyl, saturated or unsaturated, branched or unbranched,unsubstituted or mono- or polysubstituted; R^(5b) represents H or R⁰; orR^(5a) and R^(5b) form together with the carbon atom connecting them aC₃₋₁₀ cycloalkyl or a heterocyclyl, respectively saturated orunsaturated, unsubstituted or mono- or polysubstituted; R⁶, R⁷, R⁹ andR¹⁰ each independently of one another represent H; F; Cl; Br; I; NO₂;CN; CF₃; CF₂H; CFH₂; CF₂Cl; CFCl₂; R⁰; C(═O)H; C(═O)R⁰; CO₂H; C(═O)OR⁰;CONH₂; C(═O)NHR⁰; C(═O)N(R⁰)₂; OH; OCF₃; OCF₂H; OCFH₂; OCF₂Cl; OCFCl₂;OR⁰; O—C(═O)—R⁰; O—C(═O)—O—R⁰; O—(C═O)—NH—R⁰; O—C(═O)—N(R⁰)₂;O—S(═O)₂—R⁰; O—S(═O)₂OH; O—S(═O)₂OR⁰; O—S(═O)₂NH₂; O—S(═O)₂NHR⁰;O—S(═O)₂N(R⁰)₂; NH₂; NH—R⁰; N(R⁰)₂; NH—C(═O)—R⁰; NH—C(═O)—O—R⁰;NH—C(═O)—NH₂; NH—C(═O)—NH—R⁰; NH—C(═O—N(R⁰)NR⁰—C(═O)—R⁰; NR⁰—C(═O)—O—R⁰;NR⁰—C(═O)—NH₂; NR⁰—C(═O)—NH—R⁰; NR⁰—C(═O)—N(R⁰)₂; NH—S(═O)₂OH;NH—S(═O)₂R⁰; NH—S(═O)₂OR⁰; NH—S(═O)₂NH₂; NH—S(═O)₂NHR⁰; NH—S(═O)₂N(R⁰)₂;NR⁰—S(═O)₂OH; NR⁰—S(═O)₂R⁰; NR⁰—S(═O)₂OR⁰; NR⁰—S(═O)₂NH₂;NR⁰—S(═O)₂NHR⁰; NR⁰—S(═O)₂N(R⁰)₂; SH; SCF₃; SCF₂H; SCFH₂; SCF₂Cl;SCFCl₂; SR⁰; S(═O)R⁰; S(═O)₂R⁰; S(═O)₂OH; S(O)₂OR²; S(═O)₂NH₂;S(═O)₂NHR⁰; or S(═O)₂N(R⁰)₂; R⁸ represents H; F; Cl; Br; I; NO₂; CN;CF₃; CF₂H; CFH₂; CF₂Cl; CFCl₂; R⁰; C(═O)H; C(═O)R⁰; CO₂H; C(═O)OR⁰;CONH₂; C(═O)NHR⁰; C(═O)N(R⁰)₂; OH; OCF₃; OCF₂H; OCFH₂; OCF₂Cl; OCFCl₂;OR⁰; O—C(═O)—R⁰; O—C(═O)—O—R⁰; O—(C═)—NH—R⁰; O—C(═O)—N(R⁰)₂; O—S(λO)₂R⁰;O—S(═O)₂OH; O—S(═O)₂OR⁰; O—S(═O)₂NH₂; O—S(═O)₂NHR⁰; O—S(═O)₂N(R⁰)₂; NH₂;NH—R⁰; N(R⁰)₂; NH—C(═O)—R⁰; NH—C(═O)—O—R⁰; NH—C(═O)—NH₂; NH—C(═O)—NH—R⁰;NH—C(═O—N(R⁰)₂; NR⁰—C(═O)—R⁰; NR⁰—C(═O)—R⁰; NR⁰—C(═O)—NH₂;NR⁰—C(═O)—NH—R⁰; NR⁰—C(═O)—N(R⁰)₂; NH—S(═O)₂OH; NH—S(═O)₂R⁰;NH—S(λO)₂OR⁰; NH—S(═O)₂NH₂; NH—S(═O)₂NHR⁰; NH—S(═O)₂N(R⁰)₂;NR⁰—S(═O)₂OH; NR⁰—S(═O)₂R⁰; NR⁰—S(═O)₂OR⁰; NR⁰—S(═O)₂NH₂;NR⁰—S(═O)₂NHR⁰; NR⁰—S(═O)₂N(R⁰)₂; SH; SCF₃; SCF₂H; SCFH₂; SCF₂Cl;SCFCl₂; SR⁰; S(═O)R⁰; S(═O)₂R⁰; S(═O)₂OH; S(═O)₂OR⁰; S(═O)₂NH₂;S(═O)₂NHR⁰; or S(═O)₂N(R⁰)₂; wherein, if R⁸ denotes R⁰ and R⁰ representsheteroaryl, said heteroaryl is selected from the group consisting ofbenzofuranyl, benzoimidazolyl, benzothienyl, benzothiadiazolyl,benzothiazolyl, benzotriazolyl, benzooxazolyl, benzooxadiazolyl,quinazolinyl, quinoxalinyl, carbazolyl, quinolinyl, dibenzofuranyl,dibenzothienyl, furyl (furanyl), imidazothiazolyl, indazolyl,indolizinyl, indolyl, isoquinolinyl, isoxazoyl, isothiazolyl, indolyl,naphthyridinyl, oxazolyl, oxadiazolyl, phenazinyl, phenothiazinyl,phthalazinyl, pyrazolyl, pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl),pyrrolyl, pyridazinyl, pyrimidinyl, pyrazinyl, purinyl, phenazinyl,thienyl (thiophenyl), triazolyl, tetrazolyl, thiazolyl, thiadiazolyl andtriazinyl; in which “substituted alkyl”, “substituted heterocyclyl” and“substituted cycloalkyl” relate, with respect to the correspondingresidues, to the substitution of one or more hydrogen atoms eachindependently of one another by F; Cl; Br; I; NO₂; CN; ═O; ═NH;═C(NH₂)₂; CF₃; CF₂H; CFH₂; CF₂Cl; CFCl₂; R⁰; C(═O)H; C(═O)R⁰; CO₂H;C(═O)OR⁰; CONH₂; C(═O)NHR⁰; C(═O)N(R⁰)₂; OH; OCF₃; OCF₂H; OCFH₂; OCF₂Cl;OCFCl₂; OR⁰; O—C(═O)—R⁰; O—C(═O)—O—R⁰; O—(C═O)—NH—R⁰; O—C(═O)—N(R⁰)₂;O—S(═O)—R⁰; O—S(═O)₂OH; O—S(═O)₂OR⁰; O—S(═O)₂NH₂; O—S(═O)₂NHR⁰;O—S(═O)₂N(R⁰)₂; NH₂; NH—R⁰; N(R⁰)₂; NH—C(═O)—R⁰; NH—C(═O)—O—R⁰;NH—C(═O)—NH₂; NH—C(═O)—NH—R⁰; NH—C(═O)—N(R⁰)₂; NR⁰—C(═O)—R⁰;NR⁰—C(═O)—O—R⁰; NR⁰—C(═O)—NH₂; NR⁰—C(═O)—NH—R⁰; NR⁰—C(═O)—N(R⁰)₂;NH—S(═O)₂OH; NH—S(═O)₂R⁰; NH—S(═O)₂OR⁰; NH—S(═O)₂NH₂; NH—S(═O)₂NHR⁰;NH—S(═O)₂N(R⁰)₂; NR⁰—S(═O)₂OH; NR⁰—S(═O)₂R⁰; NR⁰—S(═O)₂OR⁰;NR⁰—S(═O)₂NH₂; NR⁰—S(═O)₂NHR⁰; NR⁰—S(═O)₂N(R⁰)₂; SH; SCF₃; SCF₂H; SCFH₂;SCF₂Cl; SCFCl₂; SR⁰; S(═O)R⁰; S(═O)₂R⁰; S(═O)₂OH; S(═O)₂OR⁰; S(═O)₂NH₂;S(═O)₂NHR⁰; or S(═O)₂N(R⁰)₂; in which “substituted cycloalkyl¹” and“substituted heterocyclyl¹” relate, with respect to the correspondingresidues, to the substitution of one or more hydrogen atoms eachindependently of one another by F; Cl; Br; I; NO₂; CN; ═O; ═C(NH₂)₂;CF₃; CF₂H; CFH₂; CF₂Cl; CFCl₂; R⁰; C(═O)H; C(═O)R⁰; CO₂H; C(═O)OR⁰;CONH₂; C(═O)NHR⁰; C(═O)N(R⁰)₂; OH; OCF₃; OCF₂H; OCFH₂; OCF₂Cl; OCFCl₂;OR⁰; O—C(═O)—R⁰; O—C(═O)—O—R⁰; O—(C═O)—NH—R⁰; O—C(═O)—N(R⁰)₂;O—S(═O)₂—R⁰; O—S(═O)₂OH; O—S(═O)₂OR⁰; O—S(═O)₂NH₂; O—S(═O)₂NHR⁰;O—S(═O)₂N(R⁰)₂; SH; SCF₃; SCF₂H; SCFH₂; SCF₂Cl; SCFCl₂; SR⁰; S(═O)R⁰;S(═O)₂R⁰; S(═O)₂OH; S(═O)₂OR⁰; S(═O)₂NH₂; S(═O)₂NHR⁰; or S(═O)₂N(R⁰)₂;in which “substituted aryl” relates, with respect to the correspondingresidues, to the substitution of one or more hydrogen atoms eachindependently of one another by F; Cl; Br; I; NO₂, CF₃; CF₂H; CFH₂;CF₂Cl; CFCl₂; R⁰; C(═O)H; C(═O)R⁰; CO₂H; C(═O)OR⁰; CONH₂; C(═O)NHR⁰;C(═O)N(R⁰)₂; OH; OCF₃; OCF₂H; OCFH₂; OCF₂Cl; OCFCl₂; OR⁰; O—C(═O)—R⁰;O—C(═O)—O—R⁰; O—(C═O)—NH—R⁰; O—C(═O)—N(R⁰)₂; O—S(═O)₂—R⁰; O—S(═O)₂OH;O—S(═O)₂OR⁰; O—S(═O)₂NH₂; O—S(═O)₂NHR⁰; O—S(═O)₂N(R⁰)₂; NH₂; NH—R⁰;N(R⁰)₂; NH—C(═O)—R⁰; NH—C(═O)—O—R⁰; NH—C(═O)—NH₂; NH—C(═O)—NH—R⁰;NH—C(═O)—N(R⁰)₂; NR⁰—C(═O)—R⁰; NR⁰—C(═O)—O—R⁰; NR⁰—C(═O)—NH₂;NR⁰—C(═O)—NH—R⁰; NR⁰—C(═O)—N(R⁰)₂; NH—S(═O)₂OH; NH—S(═O)₂R⁰;NH—S(═O)₂OR⁰; NH—S(═O)₂NH₂; NH—S(═O)₂NHR⁰; NH—S(═O)₂N(R⁰)₂;NR⁰—S(═O)₂OH; NR⁰—S(═O)₂R⁰; NR⁰—S(═O)₂OR⁰; NR⁰—S(═O)₂NH₂;NR⁰—S(═O)₂NHR⁰; NR⁰—S(═O)₂N(R⁰)₂; SH; SCF₃; SCF₂H; SCFH₂; SCF₂Cl;SCFCl₂; SR⁰; S(═O)R⁰; S(═O)₂R⁰; S(═O)₂OH; S(═O)₂OR⁰; S(═O)₂NH₂;S(═O)₂NHR⁰; or S(═O)₂N(R⁰)₂; in which ““substituted heteroaryl” relates,with respect to the corresponding residues, to the substitution of oneor more hydrogen atoms each independently of one another by F; Cl; Br;I; NO₂; CN; CF₃; CF₂H; CFH₂; CF₂Cl; CFCl₂; R⁰; C(═O)H; C(═O)R⁰; CO₂H;C(═O)OR⁰; CONH₂; C(═O)NHR⁰; C(═O)N(R⁰)₂; OH; OCF₃; OCF₂H; OCFH₂; OCF₂Cl;OCFCl₂; OR⁰; O—C(═O)—R⁰; O—C(═O)—O—R⁰; O—(C═O)—NH—R⁰; O—C(═O)—N(R⁰)₂;O—S(═O)₂—R⁰; O—S(═O)₂OH; O—S(═O)₂OR⁰; O—S(═O)₂NH₂; O—S(═O)₂NHR⁰;O—S(═O)₂N(R⁰)₂; NH₂; NH—R⁰; N(R⁰)₂; NH—C(═O)—R⁰; NH—C(═O)—O—R⁰;NH—C(═O)—NH₂; NH—C(═O)—NH—R⁰; NH—C(═O)—N(R⁰)₂; NR⁰—C(═O)—R⁰;NR⁰—C(═O)—O—R⁰; NR⁰—C(═O)—NH₂; NR⁰—C(═O)—NH—R⁰; NR⁰—C(═O)—N(R⁰)₂;NH—S(═O)₂OH; NH—S(═O)₂R⁰; NH—S(═O)₂OR⁰; NH—S(═O)₂NH₂; NH—S(═O)₂NHR⁰;NH—S(═O)₂N(R⁰)₂; NR⁰—S(═O)₂OH; NR⁰—S(═O)₂R⁰; NR⁰—S(═O)₂OR⁰;NR⁰—S(═O)₂NH₂; NR⁰—S(═O)₂NHR⁰; NR⁰—S(═O)₂N(R⁰)₂; SH; SCF₃; SCF₃; SCF₂H;SCFH₂; SCF₂Cl; SCFCl₂; SR⁰; S(═O)R⁰; S(═O)₂R⁰; S(═O)₂OH; S(═O)₂OR⁰;S(═O)₂NH₂; S(═O)₂NHR⁰; or S(═O)₂N(R⁰)₂; in the form of the freecompounds; the tautomers; the N-oxides; the racemate; the enantiomers,diastereomers, mixtures of the enantiomers or diastereomers or of anindividual enantiomer or diastereomer; or in the form of the salts ofphysiologically compatible acids or bases, wherein the one or moredisorders selected from the group consisting of pain; hyperalgesia;allodynia; causalgia; migraine; depression; nervous affection; axonalinjuries; neurodegenerative diseases; cognitive dysfunctions epilepsy;respiratory diseases; coughs; urinary incontinence; overactive bladder(OAB); disorders and/or injuries of the gastrointestinal tract; duodenalulcers; gastric ulcers; irritable bowel syndrome; strokes; eyeirritations; skin irritations; neurotic skin diseases; allergic skindiseases; psoriasis; vitiligo; herpes simplex; inflammations; diarrhoea;pruritus; osteoporosis; arthritis; osteoarthritis; rheumatic diseases;eating disorders; medication dependency; misuse of medication;withdrawal symptoms in medication dependency; development of toleranceto medication; drug dependency; misuse of drugs; withdrawal symptoms indrug dependency; alcohol dependency; misuse of alcohol and withdrawalsymptoms in alcohol dependency; for diuresis; for antinatriuresis; forinfluencing the cardiovascular system; for increasing vigilance; for thetreatment of wounds and/or burns; for the treatment of severed nerves;for increasing libido; for modulating movement activity; for anxiolysis;for local anaesthesia and/or undesirable side effects.
 14. Process forpreparing a compound according to claim 13, wherein at least onecompound of general formula (II),

in which X, R¹, R², R⁴ and n have a meaning according to claim 13, isreacted in a reaction medium, if appropriate in the presence of at leastone suitable coupling reagent, if appropriate in the presence of atleast one base, with a compound of general formula (III) or (IV),

in which Hal represents a halogen, preferably Cl or Br, and R^(5a),R^(5b), R⁶, R⁷, R⁸, R⁹ and R¹⁰ each have a meaning according to claim13, if appropriate in the presence of at least one suitable couplingreagent, if appropriate in the presence of at least one base, to form acompound of general formula (I),

in which A represents CR^(5b) and X, R¹, R², R⁴, R^(5a), R^(5b), R⁶, R⁷,R⁸, R⁹, R¹⁰ and n have a meaning according to claim 13; or in that atleast one compound of general formula (II),

in which X, R¹, R², R⁴ and n have a meaning according to claim 13, isreacted to form a compound of general formula (V)

in which X, R¹, R², R⁴ and n have a meaning according to claim 13, in areaction medium, in the presence of phenyl chloroformate, if appropriatein the presence of at least one base and/or a coupling reagent, and saidcompound is if appropriate purified and/or isolated, and a compound ofgeneral formula (V) is reacted with a compound of general formula (VI),

in which R⁶, R⁷, R⁸, R⁹ and R¹⁰ have a meaning according to claim 13, ina reaction medium, if appropriate in the presence of at least onesuitable coupling reagent, if appropriate in the presence of at leastone base, to form a compound of general formula (I),

in which A represents N and X, R¹, R², R⁴, R^(5a), R⁶, R⁷, R⁸ R⁹ and R¹⁰and n have a meaning according to claim
 13. 15. The method of claim 12,wherein the pain is selected from the group consisting of acute pain,chronic pain, neuropathic pain, visceral pain and joint pain.
 16. Themethod of claim 12, wherein the neurodegenerative disease is, preferablyselected from the group consisting of multiple sclerosis, Alzheimer'sdisease, Parkinson's disease and Huntington's disease.
 17. The method ofclaim 12, wherein the cognitive dysfunction is a cognitive deficiencystate.
 18. The method of claim 12, wherein the respiratory disease isselected from the group consisting of asthma, bronchitis and pulmonaryinflammation.
 19. The method of claim 12, wherein the eating disorder isselected from the group consisting of bulimia, cachexia, anorexia andobesity.
 20. The method of claim 12, wherein the development oftolerance to medication is a development of tolerance to natural orsynthetic opioids.
 21. The method of claim 12, wherein the undesirableside effect triggered by the administration of vanilloid receptor 1(VR1/TRPV1 receptor) agonists, and wherein the undesirable side effectis selected from the group consisting of hyperthermia, hypertension andbronchoconstriction.
 22. The method of claim 23 wherein the VR1/TRPV1receptor agonist is selected from the group consisting of capsaicin,resiniferatoxin, olvanil, arvanil, SDZ-249665, SDZ-249482, nuvanil andcapsavanil.
 23. The method of claim 13, wherein the pain is selectedfrom the group consisting of acute pain, chronic pain, neuropathic pain,visceral pain and joint pain.
 24. The method of claim 13, wherein theneurodegenerative disease is selected from the group consisting ofmultiple sclerosis, Alzheimer's disease, Parkinson's disease andHuntington's disease.
 25. The method of claim 13, wherein the cognitivedysfunction is a cognitive deficiency state.
 26. The method of claim 13,wherein the respiratory disease is selected from the group consisting ofasthma, bronchitis and pulmonary inflammation.
 27. The method of claim13, wherein the inflammation is an inflammation of the intestine, eye,bladder, skin, or the nasal mucous membrane.
 28. The method of claim 13,wherein the eating disorder is selected from the group consisting ofbulimia, cachexia, anorexia and obesity.
 29. The method of claim 13,wherein the development of tolerance to medication is a development oftolerance to natural or synthetic opioids.
 30. The method of claim 13,wherein the undesirable side effect is triggered by the administrationof vanilloid receptor 1 (VR1/TRPV1 receptor) agonists, and wherein theundesirable side effect is selected from the group consisting ofhyperthermia, hypertension and bronchoconstriction.
 31. The method ofclaim 33 wherein the VR1/TRPV1 receptor agonist is selected from thegroup consisting of capsaicin, resiniferatoxin, olvanil, arvanil,SDZ-249665, SDZ-249482, nuvanil and capsavanil.